Language：Japanese   Publisher：関東リウマチ研究会  

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s12185-024-03751-x

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Other Link： https://link.springer.com/article/10.1007/s12185-024-03751-x/fulltext.html

Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：English  

DOI： 10.1101/2024.01.05.24300886

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Language：Japanese   Publisher：日本リウマチ学会-関東支部  

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Language：Japanese   Publisher：日本リウマチ学会-関東支部  

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Language：Japanese   Publisher：日本リウマチ学会-関東支部  

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Language：Japanese   Publisher：日本リウマチ学会-関東支部  

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

Despite recent advances in the treatment of acute myeloid leukemia (AML), there has been limited success in targeting surface antigens in AML, in part due to shared expression across malignant and normal cells. Here, high-density immunophenotyping of AML coupled with proteogenomics identified unique expression of a variety of antigens, including the RNA helicase U5 snRNP200, on the surface of AML cells but not on normal hematopoietic precursors and skewed Fc receptor distribution in the AML immune microenvironment. Cell membrane localization of U5 snRNP200 was linked to surface expression of the Fcγ receptor IIIA (FcγIIIA, also known as CD32A) and correlated with expression of interferon-regulated immune response genes. Anti-U5 snRNP200 antibodies engaging activating Fcγ receptors were efficacious across immunocompetent AML models and were augmented by combination with azacitidine. These data provide a roadmap of AML-associated antigens with Fc receptor distribution in AML and highlight the potential for targeting the AML cell surface using Fc-optimized therapeutics.

DOI： 10.1038/s43018-023-00656-2

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Other Link： https://www.nature.com/articles/s43018-023-00656-2

Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

Abstract

O-linked N-acetylglucosamine transferase (OGT) critically regulates wide variety of biological processes such as gene expression, metabolism, stress response, signaling and proteostasis. In adult hematopoiesis, OGT is crucial for differentiation of B and T cells and the maintenance of hematopoietic stem cells (HSCs). However, a role for OGT in fetal liver (FL) hematopoiesis remains unknown. To investigate a role for OGT in FL hematopoiesis, we conditionally disrupted OGT in hematopoietic cells in developing FLs. Hematopoietic specific disruption of OGT resulted in embryonic lethality in late stage of gestation due to severe anemia and growth retardation. OGT loss led to profound reduction of differentiating erythroid cells and erythroid progenitors in FLs due to massive apoptosis. In addition, clonogenic capacity of FL cells was severely impaired by OGT loss. Interestingly, expression of BCL-XL, a well-known inhibitor of apoptosis in FL cells, dramatically decreased, and the levels of reactive oxygen species (ROS) were increased in OGT-deficient FL cells. Overexpression of Bcl-xL and reduction of ROS significantly restored the colony formation of OGT-deficient FL cells. This study revealed a novel role for OGT during embryogenesis, which ensures survival of FL hematopoietic cells partly by regulating Bcl-xL and oxidative phosphorylation.

DOI： 10.1093/stmcls/sxad076

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Language：Japanese   Publisher：(一社)日本骨粗鬆症学会  

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Language：Japanese   Publisher：(一社)日本骨粗鬆症学会  

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.2169/internalmedicine.1490-22

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Language：Japanese   Publisher：関東リウマチ研究会  

症例は54歳男性で、労作時呼吸困難を主訴とした。下腿の紅斑、大球性貧血を認め、骨髄検査よりMDSと診断した。両側肺多発結節影、多発リンパ節腫脹を認め、高拍出性心不全が出現した。炎症所見、皮膚・肺・眼の病変、骨髄検査で空砲像を認め、末梢血の遺伝子解析よりVEXAS症候群と診断した。炎症に伴う貧血・心不全のコントロールが困難であったが利尿剤、プレドニゾロン投与が奏効し、心不全の改善・CRPの改善傾向、貧血の改善を認めた。胸部CTで胸水・肺鬱血像の消失、多発肺結節影の縮小を認めた。

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Language：English   Publishing type：Research paper (scientific journal)  

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a new disease entity with autoinflammatory disorders (AID) driven by somatic variants in UBA1 that frequently co-exists with myelodysplastic syndromes (MDS). Clinicopathological and molecular features of Japanese cases with VEXAS-associated MDS remain elusive. We previously reported high prevalence of UBA1 variants in Japanese patients with relapsing polychondritis, in which 5 cases co-occurred with MDS. Here, we report clinicopathological and variant profiles of these 5 cases and 2 additional cases of MDS associated with VEXAS syndrome. Clinical characteristics of these cases included high prevalence of macrocytic anemia with marked cytoplasmic vacuoles in myeloid/erythroid precursors and low bone marrow (BM) blast percentages. All cases were classified as low or very low risk by the revised international prognostic scoring system (IPSS-R). Notably, 4 out of 7 cases showed significant improvement of anemia by treatment with prednisolone (PSL) or cyclosporin A (CsA), suggesting that an underlying inflammatory milieu induced by VEXAS syndrome may aggravate macrocytic anemia in VEXAS-associated MDS. Targeted deep sequencing of blood samples suggested that MDS associated with VEXAS syndrome tends to involve a smaller number of genes and lower risk genetic lesions than classical MDS.

DOI： 10.1007/s12185-023-03598-8

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Immune checkpoint inhibitors (ICIs) have been a breakthrough in cancer therapy. ICI therapy is generally better tolerated than cytotoxic chemotherapy; however, hematological adverse events (AEs) have not been fully analyzed. Hence, we performed a meta-analysis to evaluate the incidence and risk of ICI-related hematological AEs. METHODS: A systematic literature search was performed using PubMed, EMBASE, Cochrane Library, and the Web of Science Core Collection. Phase III randomized controlled trials (RCTs) involving ICI combination regimens were selected. The experimental group received ICIs with systemic treatment, and the control group received only the same systemic treatment. Odds ratios (ORs) for anemia, neutropenia, and thrombocytopenia were calculated using a random-model meta-analysis. RESULTS: We identified 29 RCTs with 20,033 patients. The estimated incidence rates for anemia of all grades and grades III-V were 36.5% (95% confidence interval (CI) 30.23 - 42.75) and 4.1% (95% CI 3.85 - 4.42), respectively. The incidence of neutropenia (all grades 29.7%, grades III-V 5.3%) and thrombocytopenia (all grades 18.0%, grades III-V 1.6%) was also calculated. CONCLUSION: Treatment with ICIs seemed unlikely to increase the incidence of anemia, neutropenia, and thrombocytopenia in all grades. However, programmed cell death-1 receptor ligand inhibitors significantly increased the risk of grades III-V thrombocytopenia (OR 1.53; 95% CI 1.11 - 2.11). Further research is needed to examine the potential risk factors.

DOI： 10.14740/jh1090

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVES: Infection is a leading cause of death in patients with systemic lupus erythematosus (SLE). Alt hough hydroxychloroquine (HCQ) has been reported to inhibit infection, evidence from Asian populations remains insufficient. We investigated this effect in Japanese SLE patients. METHODS: Data from the Lupus Registry of Nationwide Institutions were used in this study. The patients were ≥20 years old and met the American College of Rheumatology (ACR) classification criteria revised in 1997. We defined "severe infections" as those requiring hospitalization. We analyzed the HCQ's effect on infection suppression using a generalized estimating equation (GEE) logistic regression model as the primary endpoint and performed a survival analysis for the duration until the first severe infection. RESULTS: Data from 925 patients were used (median age, 45 [interquartile range 35-57] years; female, 88.1%). GEE analysis revealed that severe infections were significantly associated with glucocorticoid dose (odds ratio [OR] 1.968 [95% confidence interval, 1.379-2.810], p<0.001), immunosuppressants (OR 1.561 [1.025-2.380], p=0.038), and baseline age (OR 1.043 [1.027-1.060], p<0.001). HCQ tended to suppress severe infections, although not significantly (OR 0.590 [0.329-1.058], p=0.077). Survival time analysis revealed a lower incidence of severe infections in the HCQ group than in the non-HCQ group (p<0.001). In a Cox proportional hazards model, baseline age (hazard ratio [HR] 1.029 [1.009-1.050], p=0.005) and HCQ (HR 0.322 [0.142-0.728], p=0.006) were significantly related to incidence. CONCLUSION: HCQ may help extend the time until the occurrence of infection complications and tends to decrease infection rates.

DOI： 10.3389/fimmu.2023.1227403

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Language：English  

DOI： 10.2169/internalmedicine.1199-22

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Publishing type：Research paper (scientific journal)   Publisher：Informa UK Limited  

DOI： 10.1080/16078454.2022.2052601

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Language：English  

Cryptococcal meningitis (CM) is a life-threatening disease that primarily affects patients with human immunodeficiency virus (HIV). Antifungal therapy with antiretroviral treatment (ART) usually leads to the clinical remission of CM; however, in some cases, these treatments exacerbate intracranial inflammation because of paradoxical inflammatory reaction or immune reconstitution inflammatory syndrome (IRIS). Here we report two CM cases that presented atypical clinical courses attributed to paradoxical inflammatory reactions. The first case was a 43-year-old man with headache and vertigo diagnosed with CM and HIV. The patient's CM not only was refractory to the antifungal combination therapy of liposomal amphotericin B (L-AMB) and fluconazole (FLCZ) but suddenly worsened because of a paradoxical inflammatory reaction after 18 days of treatment. He passed away from brain herniation on day 23. The second case was a 43-year-old man diagnosed with CM and HIV. After receiving antifungal therapy and ART, the patient's status was stable for more than 3 years with undetectable HIV-RNA. He suddenly presented with brain inflammation and was diagnosed with IRIS due to CM (CM-IRIS). His brain lesions were migratory and refractory to various antifungal therapies such as L-AMB, FLCZ, flucytosine, and intrathecal amphotericin B. Although the cryptococcal antigen in the patient's cerebrospinal fluid gradually diminished after continuous antifungal therapies, his cognitive function declined, and right hemiparesis persisted. These two cases of CM presented atypical clinical courses, presumably because of paradoxical inflammatory reactions. It should be noted that the onset of CM-IRIS may not necessarily depend on the timing of ART initiation.

DOI： 10.1016/j.jiac.2022.11.002

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Language：Japanese   Publisher：(有)科学評論社  

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Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVES: With the increased use of immune checkpoint inhibitors (ICIs), arthralgia has been the most commonly reported musculoskeletal immune-related adverse events (irAEs). We aimed to characterise arthralgia and its association with overall survival (OS). METHODS: Randomised controlled trials (RCTs) reporting data for ICI-induced arthralgia from four online databases were comprehensively investigated. Odds ratios (OR) with 95% confidence intervals (CI) were calculated for arthralgia using a random effects model meta-analysis. Individual patient data were reconstructed from RCTs, assessing OS in patients with or without ICI-induced arthralgia. We also retrospectively collected data on the clinical features and outcomes of ICI-induced arthralgia in the Yokohama City University (YCU) registry. RESULTS: We analysed 14,377 patients from 24 RCTs. The OR of ICI-induced arthralgia was 1.37 (95% CI 1.20-1.56). Of the 369 patients in YCU registry, 50 (13.6%) developed ICI-induced arthralgia. Among them, 30 had other grade ≥2 irAEs; noticeably more frequently vs. those without arthralgia (OR 1.92, 95% CI 1.04-3.52). By irAE types, a significant difference was found for relative adrenal insufficiency (OR 3.88, 95% CI 1.80-8.39). In the YCU registry, patients with (vs. without) ICI-induced arthralgia had better OS (log-rank, P < 0.001). OS results were validated from RCT patients with matched cancer types, drugs, and time to arthralgia onset (hazard ratio 0.34, 95% CI 0.17-0.65, P < 0.001). CONCLUSION: If arthralgia develops after ICIs, another irAE, such as relative adrenal insufficiency, may have developed. The incidence of arthralgia was associated with better OS and patients' condition must be carefully evaluated to determine optimal management.

DOI： 10.1093/rheumatology/keac519

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Language：English   Publishing type：Research paper (scientific journal)  

Disseminated nontuberculous mycobacterial infection (DNTM) is typically observed in immunocompromised hosts. Recently, it has been reported that healthy individuals with serum neutralizing autoantibodies for interferon (IFN)-γ can also develop DNTM. We herein report a case of anti-IFN-γ antibody-seropositive DNTM caused by Mycobacterium kansasii with symptoms mimicking TAFRO or POEMS syndrome, including anasarca, organomegaly, skin pigmentation, polyneuropathy, osteosclerotic change, thrombocytopenia, serum M protein, high C-reactive protein level, and reticulin fibrosis. The combination of antimicrobial chemotherapy with glucocorticoid and intravenous immunoglobulin improved his symptoms. Glucocorticoids may be an effective method of suppressing the production of anti-IFN-γ antibodies in DNTM.

DOI： 10.2169/internalmedicine.8366-21

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Language：English   Publishing type：Research paper (scientific journal)  

Smoking is associated with a high risk for different diseases including respiratory tract infections in immunocompetent patients. However, data about the effects of cigarette smoking on the outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) are limited. Therefore, we retrospectively investigated 608 patients aged ≥20 years with hematological disorders who received their first allo-HSCT at our group of hospitals between 2000 and 2015, and evaluated the impact of cigarette smoking before allo-HSCT on clinical outcomes by dividing patients into two groups according to the Brinkman index (BI) (nonsmokers or light smokers [BI: 0-500] and heavy smokers [BI: ≥ 500]). Multivariate analyses showed that heavy smoking was associated with a high 5-year cumulative incidence of chronic graft-versus-host disease (cGVHD) (hazard ratio [HR]: 1.73, 95% confidence interval [CI]: 1.15-2.61, p < 0.01). The 5-year overall survival (HR: 1.16, 95% CI: 0.86-1.58, p = 0.33) and disease-free survival (HR: 1.12, 95% CI: 0.83-1.52, p = 0.45) were similar between the two groups. Hence, cigarette smoking is correlated with cGVHD, although prospective studies must be conducted to further verify this result.

DOI： 10.1038/s41409-022-01678-7

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Publishing type：Research paper (scientific journal)   Publisher：American Society of Hematology  

Detailed genomic and epigenomic analyses of MECOM (the MDS1 and EVI1 complex locus) have revealed that inversion or translocation of chromosome 3 drive inv(3)/t(3;3) myeloid leukemias via structural rearrangement of an enhancer which upregulates transcription of EVI1. Here we identify a novel, previously unannotated oncogenic RNA-splicing derived isoform of EVI1 which is frequently present in inv(3)/t(3;3) AML and directly contributes to leukemic transformation. This EVI1 isoform is generated by oncogenic mutations in the core RNA splicing factor SF3B1, which is mutated in &amp;gt;30% of inv(3)/t(3;3) myeloid neoplasm patients and thereby represents the single most commonly co-occurring genomic alteration in inv(3)/t(3;3) patients. SF3B1 mutations are statistically uniquely enriched in inv(3)/t(3;3) myeloid neoplasm patients and patient-derived cell lines compared with other forms of AML and promote mis-splicing of EVI1 generating an in-frame insertion of six amino acids at the 3' end of the second Zinc finger domain of EVI1. Expression of this EVI1 splice variant enhanced the self-renewal of hematopoietic stem cells and introduction of mutant SF3B1 in mice bearing the humanized inv(3)(q21q26) allele resulted in generation of this novel EVI1 isoform in mice and hastened leukemogenesis in vivo. The mutant SF3B1 spliceosome depends upon an exonic splicing enhancer within EVI1 exon 13 to promote usage of a cryptic branch point and aberrant 3' splice site within intron 12 resulting in the generation of this isoform. These data provide a mechanistic basis for the frequent co-occurrence of SF3B1 mutations as well as new insights into the pathogenesis of myeloid leukemias harboring inv(3)/t(3;3).

DOI： 10.1182/blood.2021015325

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Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVES: We aimed to evaluate the efficacy and safety of hematopoietic stem cell transplantation (HSCT) in patients with systemic sclerosis (SSc). METHODS: A systematic literature review and meta-analysis were carried out. We compared survival outcomes using the Kaplan-Meier method with patient-level data between HSCT and intravenous pulse cyclophosphamide (IVCY). Additionally, the incidence rate of treatment-related deaths with HSCT was pooled using a random-effect model. RESULTS: Of the 2,091 articles screened, 22 were included: 3 randomized controlled trials and 19 observational studies. HSCT studies showed significant improvement in the skin thickness score and lung function. Despite treatment-related deaths being higher in HSCT than in IVCY, the Kaplan-Meier analysis showed a high survival rate 2 years post-transplant (log-rank, P=0.004). The pooled frequency of transplant-related death from 700 SSc patients was 6.30% (95% confidence interval 4.21-8.38). However, the estimated frequency of treatment-related deaths has been reducing over the last decade. CONCLUSION: HSCT is an effective treatment for SSc, but the optimal indications must be carefully determined by balancing the risks.

DOI： 10.1093/mr/roac026

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：English   Publishing type：Research paper (scientific journal)  

Behçet's disease (BD) is a systemic inflammatory disease characterized by recurrent oral ulcers, genital ulcers, cutaneous inflammation, and uveitis. In addition, other potentially life-threatening lesions may occur in the intestinal tract, blood vessels, and central nervous system. This heterogeneity of the BD phenotype hampers development of a targeted treatment strategy. The pathogenesis of BD is not fully elucidated, but it is likely that genetically susceptible people develop BD in response to environmental factors, such as microbiome factors. Genetic analyses have identified various BD susceptibility loci that function in HLA-antigen presentation pathways, Th1 and Th17 cells, and autoinflammation related to monocytes/macrophages, or that increase levels of pro-inflammatory cytokines, reduce levels of anti-inflammatory cytokines, or act in dysfunctional mucous barriers. Our functional analyses have revealed that impairment of M2 monocyte/macrophage-mediated anti-inflammatory function through IL-10 is crucial to BD pathogenesis. We, therefore, propose that BD is an M1-dominant disease. In this review, we describe the roles of monocytes and macrophages in BD and consider the potential of these cells as therapeutic targets.

DOI： 10.3389/fimmu.2022.852297

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：Japanese   Publisher：関東リウマチ研究会  

73歳男性。造影CTで膵尾部腫大、大動脈周囲の腫瘤性病変を認め、IgG4関連疾患を疑った。臨床検査、画像所見、病理組織所見で大動脈周囲炎、間質性肺炎、自己免疫膵炎を認めたが、血清IgG4は正常範囲で、病理所見はIgG4関連疾患の分類基準を満たさなかった。第19病日の造影CT、血液検査、臨床経過よりIgG4関連疾患で、大動脈周囲炎と間質性肺炎を合併したIgG4陰性自己免疫性膵炎と診断した。プレドニゾロンを開始した結果、膵酵素は速やかに改善し、膵炎および大動脈周囲炎も改善した。

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

The prognosis of rheumatic diseases is generally better than that of malignant diseases. However, some cases with poor prognoses resist conventional therapies and cause irreversible functional and organ damage. In recent years, there has been much research on regenerative medicine, which uses stem cells to restore the function of missing or dysfunctional tissues and organs. The development of regenerative medicine is also being attempted in rheumatic diseases. In diseases such as systemic sclerosis (SSc), systemic lupus erythematosus (SLE), and rheumatoid arthritis, hematopoietic stem cell transplantation has been attempted to correct and reconstruct abnormalities in the immune system. Mesenchymal stem cells (MSCs) have also been tried for the treatment of refractory skin ulcers in SSc using the ability of MSCs to differentiate into vascular endothelial cells and for the treatment of systemic lupus erythematosus SLE using the immunosuppressive effect of MSCs. CD34-positive endothelial progenitor cells (EPCs), which are found in the mononuclear cell fraction of bone marrow and peripheral blood, can differentiate into vascular endothelial cells at the site of ischemia. Therefore, EPCs have been used in research on vascular regeneration therapy for patients with severe lower limb ischemia caused by rheumatic diseases such as SSc. Since the first report of induced pluripotent stem cells (iPSCs) in 2007, research on regenerative medicine using iPSCs has been actively conducted, and their application to rheumatic diseases is expected. However, there are many safety issues and bioethical issues involved in regenerative medicine research, and it is essential to resolve these issues for practical application and spread of regenerative medicine in the future. The environment surrounding regenerative medicine research is changing drastically, and the required expertise is becoming higher. This paper outlines the current status and challenges of regenerative medicine in rheumatic diseases.

DOI： 10.3389/fmed.2022.813952

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Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Internal Medicine  

DOI： 10.2169/internalmedicine.9471-22

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Language：English  

Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is an autoinflammatory disease caused by somatic variants in the UBA1 gene that lead to severe systemic inflammation and myelodysplastic syndrome. Although no standard therapy has been established yet, azacitidine and bone marrow transplantation have been reported to be promising possibilities; however, the indications for these treatments are problematic and not necessarily applicable to all patients. We previously reported the results of short-term treatment with tocilizumab (TCZ) and glucocorticoids in three patients with VEXAS syndrome. In this paper, we report that the combination of TCZ and glucocorticoids allowed the patients to continue treatment for at least one year without significant disease progression. Glucocorticoids were able to be reduced from the start of TCZ. Adverse events were herpes zoster, skin ulceration after cellulitis, and decreased blood counts. The results suggest the significance of this treatment as a bridge therapy for the development of future therapies.

DOI： 10.3389/fimmu.2022.901063

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Language：English   Publishing type：Research paper (scientific journal)  

Pyrin/TRIM20 is expressed in the neutrophils and monocytes/macrophages and regulates caspase-1 activation and interleukin-1β maturation. Although the mutations in the PRY/SPRY domain of pyrin cause familial Mediterranean fever (FMF), the mechanism of how mutated pyrin provokes excessive inflammation in FMF patients is not well understood. The present study investigated the role of pyrin/TRIM20 in inflammation and the pathogenesis of FMF. β2-Microglobulin (β2MG) was identified as the novel pyrin ligand binding to the PRY/SPRY domain by yeast two-hybrid screenings and co-immunoprecipitation analysis. β2MG was co-localized with pyrin not only in the HEK293 cells overexpressing these proteins but also in the monosodium urate-stimulated human neutrophils in the speck-like structures. The pyrin-β2MG interaction triggered the binding of pyrin and proline-serine-threonine phosphatase interacting protein 1 (PSTPIP1) and then the subsequent recruitment of apoptosis-associated speck-like protein containing caspase recruitment domain (ASC). Caspase-1 p20 subunit, produced by pyrin inflammasome, also interacted with the pyrin PRY/SPRY domain and inhibited the pyrin-β2MG interaction. FMF-associated pyrin mutation M694V did not affect pyrin-β2MG interaction but weakened this inhibition. Our findings suggest that β2MG functions as the pyrin ligand inducing pyrin inflammasome formation and that the FMF-associated pyrin mutations weakened negative feedback of caspase-1 p20 subunit.

DOI： 10.1038/s41598-021-03073-6

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

<title>Abstract</title>The transcription factor IRF5 has been implicated as a therapeutic target for the autoimmune disease systemic lupus erythematosus (SLE). However, IRF5 activation status during the disease course and the effects of IRF5 inhibition after disease onset are unclear. Here, we show that SLE patients in both the active and remission phase have aberrant activation of IRF5 and interferon-stimulated genes. Partial inhibition of IRF5 is superior to full inhibition of type I interferon signaling in suppressing disease in a mouse model of SLE, possibly due to the function of IRF5 in oxidative phosphorylation. We further demonstrate that inhibition of IRF5 via conditional <italic>Irf5</italic> deletion and a newly developed small-molecule inhibitor of IRF5 after disease onset suppresses disease progression and is effective for maintenance of remission in mice. These results suggest that IRF5 inhibition might overcome the limitations of current SLE therapies, thus promoting drug discovery research on IRF5 inhibitors.

DOI： 10.1038/s41467-021-24609-4

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Other Link： http://www.nature.com/articles/s41467-021-24609-4

Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

We conducted population pharmacokinetic (PPK) analysis and Monte Carlo simulations to determine the appropriate prophylactic dose of fluconazole to prevent invasive candidiasis in patients with hematological malignancies. Patients receiving chemotherapy or hematopoietic stem cell transplantation at Yokohama City University Hospital between November 2018 and March 2020 were included. Additionally, patients receiving oral fluconazole for prophylaxis were recruited. We set the free area under the curve/minimum inhibitory concentration (MIC) = 50 as the target and determined the largest MIC (breakpoint MIC) that could achieve more than 90% probability of target attainment. The blood fluconazole concentration of 54 patients (119 points) was used for PPK analysis. The optimal model was the one-compartment model with first-order administration and first-order elimination incorporating creatinine clearance (CLcr) as a covariate of clearance and body weight as a covariate of distribution volume. We conducted Monte Carlo simulation with fluconazole at 200 mg/day or 400 mg/day dosing schedules and patient body weight and CLcr ranging from 40 to 70 kg and 40–140 mL/min, respectively. The breakpoint MICs on the first dosing day and at steady state were 0.5–1.0 μg/mL and 1.0–2.0 μg/mL for 200 mg/day and 1.0–2.0 μg/mL and 2.0–4.0 μg/mL for 400 mg/day, respectively. The recommended dose was 400–700 mg/day for the loading dose and 200–400 mg/day for the maintenance dose. Our findings suggest that the optimal prophylactic dose of fluconazole in hematological malignancy patients depends on CLcr and body weight, and a sufficient loading and maintenance dose may be needed to completely prevent invasive candidiasis.

DOI： 10.3390/jof7110975

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Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: This study aimed to determine the clinical efficacy of apremilast for oral ulcers, extra-oral manifestations, and overall disease activity in patients with Behçet's disease (BD). METHODS: A systematic literature search was performed in PubMed, EMBASE, Cochrane Library, and Web of Science Core Collection. Studies assessing the treatment effects of apremilast in BD were included. The odds ratios (ORs) of being symptom free for individual manifestations and mean difference (MD) of Behçet's Disease Current Activity Form (BDCAF) scores were calculated with 95% confidence intervals (CIs) at 12 and 24 weeks using a random-model meta-analysis. RESULTS: Of 259 screened articles, eight were included. After 12 weeks of apremilast treatment the OR of symptom-free was as followings: oral ulcers, 45.76 (95% CI, 13.23-158.31); genital ulcers, 4.56 (95% CI, 2.47-8.44); erythema nodosum, 3.59 (95% CI, 1.11-11.61); pseudofolliculitis, 2.81 (95% CI, 1.29-6.15); and arthritis, 3.55 (95% CI, 1.71-7.40). Furthermore, BDCAF scores at 12 weeks were significantly reduced (MD=-1.38; -1.78 to -0.99). However, the proportion of oral-ulcer free patients increased at 24 weeks (OR=14.88; 4.81 to 46.07). CONCLUSION: The currently accumulated data indicates an improvement in mucocutaneous and articular symptoms by short-term apremilast treatment in patients with BD.

DOI： 10.1093/mr/roab098

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Publishing type：Research paper (scientific journal)   Publisher：BMJ  

DOI： 10.1136/annrheumdis-2021-220876

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Publishing type：Research paper (scientific journal)   Publisher：Informa UK Limited  

DOI： 10.1080/10428194.2020.1837366

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Blackwell Publishing Ltd  

Regulation of genome-wide DNA methylation is fundamental for a variety of biological processes such as mammalian development, stem cell function, cellular proliferation/differentiation, and oncogenesis. Among the regulators of DNA methylation, ten-eleven translocation 2 (TET2) is one of the most frequently mutated genes in clonal hematopoiesis of indeterminate potential and in various hematological malignancies, underscoring a pivotal role for TET2 in blood homeostasis and hematopoietic transformation. TET2 oxidizes methylated cytosines to further modify cytosines, which behave as intermediates in active/passive DNA demethylation processes. TET2 itself associates with histone modifiers, thereby regulating histone modifications and expression of target genes. A number of studies have reported pleiotropic effects of TET2 on hematopoietic stem cell self-renewal, hematopoietic differentiation, genome instability and inflammatory response. Recent single-cell genomics studies have identified gene promoters as well as transcription factor binding sites as TET2-targeted genetic loci in which disruption of DNA methylation can fundamentally modify hematopoietic differentiation and promote leukemogenesis. TET2 mutations show convergent cooperativity with other disease alleles in signaling molecules, epigenetic modifiers, and spliceosome factors in hematopoietic transformation. Future studies focusing on the molecular basis of stem cell and immune regulation by TET2 loss will further deepen our understanding of the entire landscape of pathophysiology and molecular vulnerabilities of TET2-mutated hematological malignancies.

DOI： 10.1111/cas.14688

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O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) is a unique enzyme introducing O-GlcNAc moiety on target proteins, and it critically regulates various cellular processes in diverse cell types. However, its roles in hematopoietic stem and progenitor cells (HSPCs) remain elusive. Here, using Ogt conditional knockout mice, we show that OGT is essential for HSPCs. Ogt is highly expressed in HSPCs, and its disruption induces rapid loss of HSPCs with increased reactive oxygen species and apoptosis. In particular, Ogt-deficient hematopoietic stem cells (HSCs) lose quiescence, cannot be maintained in vivo, and become vulnerable to regenerative and competitive stress. Interestingly, Ogt-deficient HSCs accumulate defective mitochondria due to impaired mitophagy with decreased key mitophagy regulator, Pink1, through dysregulation of H3K4me3. Furthermore, overexpression of PINK1 restores mitophagy and the number of Ogt-deficient HSCs. Collectively, our results reveal that OGT critically regulates maintenance and stress response of HSCs by ensuring mitochondrial quality through PINK1-dependent mitophagy.

DOI： 10.1016/j.celrep.2020.108579

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SAGE Publications Ltd  

Background: TRIM21 is a member of the tripartite motif family proteins and is one of the autoantigens which react with anti-SS-A antibody (Ab) present in sera of patients with systemic lupus erythematosus (SLE) and Sjögren’s syndrome. Previous studies have shown that TRIM21 dysfunction promotes aberrant B-cell differentiation and Ab production in SLE, and anti-TRIM21 Ab may be related to the TRIM21 dysfunction in human SLE pathogenesis. Here, we examined the relationship between anti-TRIM21 Ab and clinical and immunological characteristics in SLE patients. Methods: Twenty-seven patients with SLE (23 women and four men) before immunosuppressive therapies, who fulfilled the revised 1997 American College of Rheumatology criteria for SLE, and four healthy controls (3 women and one man) were enrolled in the study. SLE patients were divided into two groups according to the seropositivity for anti-TRIM21 Ab. Serum anti-TRIM21 Ab levels were measured using enzyme-linked immunosorbent assays. The serum levels of cytokines and immunoglobulins were measured by cytometer beads arrays. The expression levels of TRIM21 protein in peripheral mononuclear cells (PBMCs) from SLE patients were evaluated by Western blotting. Results: Sixteen and 9 patients showed seronegativity and seropositivity for anti-TRIM21 Ab, respectively. There were no significant differences in the background parameters, including female ratio, age, disease duration, SLE activity, and laboratory data between the two groups. The serum levels of interferon (IFN)-β were significantly higher in patients with anti-TRIM21 Ab as compared with those without anti-TRIM21 Ab (P =.043). The levels of IgG1 and IgA were significantly higher in SLE patients with anti-TRIM21 Ab as compared with those without anti-TRIM21 Ab (P =.0022 and.032, respectively). The PBMCs of patients with anti-TRIM21 Ab showed a significantly lower expression of TRIM21 protein as compared with those of patients without anti-TRIM21 Ab (P =.014). Conclusions: Anti-TRIM21 Ab seropositivity was related to B-cell abnormalities and type I IFN overproduction in SLE patients. These findings suggest that anti-TRIM21 Ab may have an inhibitory effect on TRIM21 functions and be a novel biomarker for the level of dependence on type I IFN overproduction and B-cell abnormalities.

DOI： 10.1177/09612033211042293

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Taylor and Francis Ltd.  

Objective: To determine the real-world short-term efficacy and safety of apremilast for Behçet’s disease (BD). Methods: The study included patients who received apremilast for refractory oral ulcers in addition to meeting International Study Group criteria for BD or the revised International Criteria for Behçet’s Disease. To assess the efficacy of apremilast, Behçet’s disease current activity form (BDCAF) and patients’ self-perception of their disease activity were monitored for three months. The disease phenotypes, laboratory data, concomitant medication use, and adverse events were also investigated. Results: Fourteen BD patients were included in the study. Concomitant drug use were as follows: colchicine 92.9%, prednisolone 21.4%, immunosuppressants 28.6%, and tumor-necrosis inhibitor 14.3%. Oral ulcers and BDCAF scores at 3 months showed significant improvement compared to baseline. Adverse events during the study were diarrhea (n = 3, 21.4%), nausea (n = 3, 21.4%), music hallucination (n = 1, 7.1%), and branch retinal vein occlusion (n = 1, 7.1%). Apremilast was discontinued in 1 patient (7.1%) due to nausea. Conclusion: Significant improvement in oral ulcer and BDCAF with apremilast was confirmed in real-world BD patients after 3 months. The combination of colchicine and apremilast appears to be well tolerated in BD in the short-term.

DOI： 10.1080/14397595.2020.1830504

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Immune checkpoint inhibitor (ICI)-related myositis is a rare, potentially fatal condition that warrants further studies. Its incidence, clinical features, and prognosis remain poorly understood. To address these gaps, we conducted a systematic review and meta-analysis to evaluate the risk of myositis associated with ICI for solid tumors by analyzing phase III randomized controlled trials of anti-programmed death-1/ligand-1 (PD-1/PD-L1) and anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4). To complement this analysis with clinical data, we evaluated published ICI case reports along with cases from our institutional registry. This registry comprised 422 patients treated with ICIs alone or in combination from September 2014 to June 2021. The analysis revealed an incidence of ICI-related myositis in 6,838 patients in 18 randomized controlled trials of 0.38% (odds ratio 1.96; 95% confidence interval 1.02-3.75) for patients receiving ICIs compared with controls. Detailed analysis of 88 cases from the literature search and our registry showed that myositis induced by PD-1 inhibitors was more frequent than that induced by anti-CTLA-4 agents, revealing a clinically diverse trend including myasthenia gravis and myocarditis. Importantly, having ptosis at the time of onset was significantly associated with the development of concomitant myocarditis (odds ratio 3.81; 95% CI 1.48-9.83), which is associated with poor prognosis. Regarding treatment, most patients received glucocorticoids, and some received immunosuppressants. Our study revealed the incidence of ICI-mediated myositis and the clinical features of myocarditis, highlighting the need for recognition and early intervention.

DOI： 10.3389/fimmu.2021.803410

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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DOI： 10.1080/24725625.2019.1649857

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DOI： 10.1111/1756-185X.13692

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BACKGROUND: Haploinsufficiency of A20 (HA20) is caused by loss-of-function TNFAIP3 variants. Phenotypic and genetic features of HA20 remain uncertain; therefore, the clinical distinction between HA20 and Behçet's disease (BD) requires clarification. METHODS: We have collected 12 Japanese BD-like families. Probands of these families were analyzed by whole exome sequencing (WES) and subsequent Sanger sequencing. Clinical features were compared between 54 HA20 patients (including previously reported and new cases) and 520 Japanese BD patients. RESULTS: We identified c.1434C>A:p.(Cys478*) in one family and a 236 kb deletion at 6q23.3 containing TNFAIP3 in another family. Four HA20 patients in the two families presented with childhood-onset recurrent oral and genital ulcers and were initially diagnosed and treated as BD. Consistent with the clinical features of HA20, recurrent, refractory fever attacks (three of four patients), and digestive ulcers (two of the four patients) were observed. A comparison of clinical features between HA20 patients and cohorts of BD patients revealed several critical features specific to HA20. These were early-onset, familial occurrence, recurrent fever attacks, gastrointestinal involvement, and infrequent ocular involvement. CONCLUSIONS: We identified a novel nonsense variant and deletion of the entire TNFAIP3 gene in two unrelated Japanese HA20 families. Genetic screening of TNFAIP3 should be considered for familial BD-like patients with early-onset recurrent fevers.

DOI： 10.1186/s13075-019-1928-5

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DOI： 10.1253/circj.CJ-18-1044

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DOI： 10.1080/14397595.2019.1661584

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DOI： 10.1080/14397595.2018.1436028

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DOI： 10.1007/978-3-540-75387-2_66

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DOI： 10.1186/s13075-018-1613-0

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DOI： 10.1186/s13075-018-1568-1

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BACKGROUND AND AIMS: The components of the renin-angiotensin system in leukocytes is involved in the pathophysiology of non-communicable diseases (NCDs), including hypertension, atherosclerosis and chronic kidney disease. Angiotensin II type 1 receptor (AT1R)-associated protein (ATRAP) is an AT1R-specific binding protein, and is able to inhibit the pathological activation of AT1R signaling in certain animal models of NCDs. The aim of the present study was to investigate the expression and regulation of ATRAP in leukocytes. METHODS: Human leukocyte ATRAP mRNA was measured with droplet digital polymerase chain reaction system, and analyzed in relation to the clinical variables. We also examined the leukocyte cytokines mRNA in bone-marrow ATRAP-deficient and wild-type chimeric mice after injection of low-dose lipopolysaccharide. RESULTS: The ATRAP mRNA was abundantly expressed in leukocytes, predominantly granulocytes and monocytes, of healthy subjects. In 86 outpatients with NCDs, leukocyte ATRAP mRNA levels correlated positively with granulocyte and monocyte counts and serum C-reactive protein levels. These positive relationships remained significant even after adjustment. Furthermore, the leukocyte ATRAP mRNA was significantly associated with the interleukin-1β, tumor necrosis factor-α and monocyte chemotactic protein-1 mRNA levels in leukocytes of NCDs patients. In addition, the leukocyte interleukin-1β mRNA level was significantly upregulated in bone marrow ATRAP-deficient chimeric mice in comparison to wild-type chimeric mice after injection of lipopolysaccharide. CONCLUSIONS: These results suggest that leukocyte ATRAP is an emerging marker capable of reflecting the systemic and leukocyte inflammatory profile, and plays a role as an anti-inflammatory factor in the pathophysiology of NCDs.

DOI： 10.1016/j.atherosclerosis.2018.01.013

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DOI： 10.1093/rheumatology/kex036

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DOI： 10.1186/s13075-017-1506-7

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

Recent genetic analyses have revealed that premalignant somatic mutations in hematopoietic cells are common in older people without an evidence of hematologic malignancies, leading to clonal hematopoietic expansion. This phenomenon has been termed clonal hematopoiesis of indeterminate potential (CHIP). Frequency of such clonal somatic mutations increases with age: in 5-10% of people older than 70 years and around 20% of people older than 90 years. The most commonly mutated genes found in individuals with CHIP were epigenetic regulators, including DNA methyltransferase 3A (DNMT3A), Ten-eleven-translocation 2 (TET2), and Additional sex combs-like 1 (ASXL1), which are also recurrently mutated in myeloid malignancies. Recent functional studies have uncovered pleiotropic effect of mutations in DNMT3A, TET2, and ASXL1 in hematopoietic stem cell regulation and leukemic transformation. Of note, CHIP is associated with an increased risk of hematologic malignancy and all-cause mortality, albeit the annual risk of leukemic transformation was relatively low (0.5-1%). These findings suggest that clonal hematopoiesis per se may not be sufficient to engender preleukemic state. Further studies are required to decipher the exact mechanism by which preleukemic stem cells originate and transform into a full-blown leukemic state.

DOI： 10.1007/s12185-017-2257-6

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

The prognosis for disease relapse after first hematopoietic cell transplantation (HCT1) is poor. Here, we present a retrospective multicenter study to evaluate the clinical outcome and the prognostic factors for second hematopoietic cell transplantation (HCT2). The cohort in this study comprised 60 patients diagnosed with acute leukemia, who underwent HCT2 due to hematological relapse after HCT1. The overall survival (OS) at two years, non-relapse mortality (NRM), and relapse mortality (RM) were 30.3%, 40.9%, and 28.8%, respectively. Multivariate analysis for OS identified the use of a donor other than matched-related (MR) donor (hazard ratios [HR]=4.10, 95% confidence intervals [CI]: 1.72-9.74, p=.001) and high disease status (HR=2.90, 95% CI: 1.28-6.56, p=.011) as the adverse risk factors for HCT2. On analyzing the combination of factors during HCT1 and HCT2, MR donor, reduced intensity conditioning regimen, and standard status were found to be significant as favorable prognostic factors for OS. Therefore, evaluating these prognostic factors would be helpful in taking decisions regarding post-relapse management.

DOI： 10.1080/10428194.2016.1243678

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

Body mass index (BMI), which represents the proportion of weight to height, is a controversial prognostic factor for acute myeloid leukemia (AML). We evaluated prognostic value of BMI in Japanese AML. The study included 369 adult patients with newly diagnosed AML who were administered either daunorubicin or idarubicin with cytarabine as induction chemotherapy. The patients were categorized into two groups according to their BMI: the NW group (BMI &lt; 25.0 kg/m(2); normal and underweight) and OW group (BMI &gt;= 25.0 kg/m(2); overweight and obese). We analyzed treatment efficacy and toxicity of induction chemotherapy, and survival outcomes in each group. Patients in the OW group showed a better complete remission rate than the NW group (86.1 versus 76.5%, P = 0.045), no early death (0.0 versus 4.1%, P = 0.042), and better overall survival (OS) at 3 years (62.2 versus 50.1%, P = 0.012). Multivariate analysis showed BMI is an independent prognostic factor for OS (hazard ratio 0.62, 95% confidence interval 0.42-0.92, P = 0.017). These results indicate the prognostic value of BMI in adult AML patients.

DOI： 10.1007/s12185-017-2183-7

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DOI： 10.1080/14397595.2016.1222650

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Objectives: To investigate whether on-demand ultrasonography (US) assessment alongside a routine examination is useful in the management of rheumatoid arthritis (RA).Methods: US was performed in eight (bilateral MCP 2, 3, wrist and knee) joints as the routine in a cumulative total of 406 RA patients. The most symptomatic joint other than the routine joints was additionally scanned. Power Doppler (PD) and gray-scale images were scored semiquantitatively. Eight-joint scores were calculated as the sum of individual scores for the routine joints.Results: The most symptomatic joint was found among the routine joints in 209 patients (Group A) and in other joints in 148 (Group B). The PD scores of the most symptomatic joint correlated well with the 8-joint scores in Group A (r(s)=0.66), but not in Group B (r(s)=0.33). The sensitivity and specificity of assessment of the most symptomatic joint for routine assessment positivity were high (84.0% and 100%, respectively) in Group A, but low (50.0% and 61.8%, respectively) in Group B. Additional examination detected synovitis in 38% of Group B with negative results in the routine.Conclusions: On-demand US assessment in the most symptomatic joint, combined with the routine assessment, is useful for detecting RA synovitis.

DOI： 10.1080/14397595.2016.1206173

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Language：English   Publisher：(一社)日本リウマチ学会  

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DOI： 10.1080/24725625.2017.1291176

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Language：English   Publisher：AMER SOC HEMATOLOGY  

DOI： 10.1182/blood.V128.22.2795.2795

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Language：English   Publisher：AMER SOC HEMATOLOGY  

DOI： 10.1182/blood.V128.22.1616.1616

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DOI： 10.1186/s13075-016-1115-x

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DOI： 10.2169/internalmedicine.55.6297

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

A nationwide survey of inherited platelet disorder with suspected predisposition to hematological malignancies clarified the difficulty in accurately diagnosing FPD/AML based on clinical information alone. Our survey also identified additional forms of familial thrombocytopenia and MD. A computer-aided simulation implied that there is a genetic predisposition to immune thrombocytopenia.Inherited thrombocytopenia (IT) contains several forms of familial thrombocytopenia and some of them have propensity to hematological malignancies. The etiological and genetic features of this heterogeneous syndrome have not yet been elucidated.
We conducted a nationwide survey to collect clinical information and samples from patients with familial thrombocytopenia and/or hematological malignancies in order to obtain a comprehensive understanding of IT.
Among the 43 pedigrees with clinical samples, RUNX1 mutations were identified in 8 pedigrees (18.6%). While MYH9 and ANKRD26 mutations were identified in 2 and 1 pedigrees, respectively, no gene mutations were detected in the remaining 32 pedigrees from a panel of previously reported pathogenetic mutations. Clinical data were comparable between FPD/AML and non-FPD/AML probands.
Our study clarified that it is unexpectedly difficult to diagnose FPD/AML based on clinical information alone, and thus, genetic testing is strongly recommended. Our survey also identified some pedigrees with a strong family history of myelodysplastic syndromes of unknown origin. Additionally, there were 14 pedigrees in which three or more members were affected by immune thrombocytopenia (ITP), and a computer-aided simulation suggested that such a distribution almost never happens by coincidence, which implicates a genetic predisposition to ITP.

DOI： 10.1093/annonc/mdw066

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Language：English   Publisher：WILEY-BLACKWELL  

DOI： 10.1111/ctr.12702

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Language：English   Publisher：NATURE PUBLISHING GROUP  

DOI： 10.1038/bcj.2015.81

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Language：English   Publisher：NATURE PUBLISHING GROUP  

RUNX1/AML1 is among the most commonly mutated genes in human leukemia. Haploinsufficiency of RUNX1 causes familial platelet disorder with predisposition to myeloid malignancies (FPD/MM). However, the molecular mechanism of FPD/MM remains unknown. Here we show that murine Runx1(+/-) hematopoietic cells are hypersensitive to granulocyte colony-stimulating factor (G-CSF), leading to enhanced expansion and mobilization of stem/progenitor cells and myeloid differentiation block. Upon G-CSF stimulation, Runx1(+/-) cells exhibited a more pronounced phosphorylation of STAT3 as compared with Runx1(+/+) cells, which may be due to reduced expression of Pias3, a key negative regulator of STAT3 signaling, and reduced physical sequestration of STAT3 by RUNX1. Most importantly, blood cells from a FPD patient with RUNX1 mutation exhibited similar G-CSF hypersensitivity. Taken together, Runx1 haploinsufficiency appears to predispose FPD patients to MM by expanding the pool of stem/progenitor cells and blocking myeloid differentiation in response to G-CSF.

DOI： 10.1038/bcj.2015.105

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Language：English   Publisher：日本癌学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

Tyrosine kinase inhibitor (TKI) treatment has dramatically improved the outcome of chronic myelogenous leukemia in the chronic phase (CML-CP). However, one study has reported a less favorable treatment outcome with TKIs in adolescents and young adults (AYA) when compared with older patients. In the present study, we retrospectively reviewed the response to TKIs in a Japanese population of 133 CML-CP patients divided into an AYA group (n = 19) and an older group (n = 114). At diagnosis, AYA patients presented with higher white blood cell counts and lower percentage of basophils, and with lower Hasford scores, but no difference was observed in EUTOS score. Probability of achieving complete cytogenetic response was not statistically different between the groups. However, the probabilities of achieving major and complete molecular responses were significantly lower in the AYA group compared to the older group (61 vs 87 % and 17 vs. 33 % at 24 months, respectively; P &lt; 0.05). In addition, a 7-year event-free survival was significantly lower in the AYA compared to the older adults (58 vs. 80 %, P &lt; 0.05). These results suggest that AYA Japanese patients with CML-CP tend to have an unfavorable outcome on treatment with TKI.

DOI： 10.1007/s12185-015-1840-y

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

To evaluate the efficacy and safety of a combined regimen of bendamustine (B) and rituximab (R) in Japanese patients with relapsed/refractory (r/r) indolent B-cell non-Hodgkin lymphomas (B-NHLs) and mantle cell lymphoma (MCL). Patients aged 20-79 years with pathologically confirmed B-NHLs or MCL, which were r/r after 1-2 R-containing regimens, were included in this study. The BR regimen consisted of B (90 mg/m(2)) for two consecutive days and R (375 mg/m(2)) on day 1, 2, or 3. The course was repeated every 4 weeks for up to four cycles. Fifty-three patients were enrolled in this study and analyzed. The diagnosis included follicular lymphoma (FL) (77 %), mucosa-associated lymphoid tissue lymphoma (13 %) and others (10 %). Forty-seven (90 %) patients completed four cycles of treatment as per schedule. Best overall response rate (ORR) and complete response rate (CRR) was 94 and 71 %, respectively (for FL, ORR 95 % and CRR 80 %). The treatment was well tolerated and the primary toxicity was myelosuppression; the incidence of grade 3/4 leukopenia and neutropenia were 42 and 40 %, respectively. There were no grade 5 toxicities. The BR regimen is safe in Japanese patients with r/r indolent B-NHLs and MCL, and is effective for those with r/r indolent B-NHLs. For the evaluation of late toxicity, especially infection, longer follow-up of this cohort is needed.

DOI： 10.1007/s12185-015-1767-3

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A 36-year-old man with diffuse large B-cell lymphoma presented with polyneuropathy, and the diagnostic work-up revealed the presence of IgM antibodies against gangliosides with disialosyl residues (GD1b, GD3). He was treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone and received high-dose intravenous immunoglobulin for the treatment of neuropathy. After initiating the treatments, the patient's neurological impairment improved dramatically. He currently remains in complete remission without a flare-up of the polyneuropathy. Based upon our experience and other case reports of lymphoma with immune-mediated neuropathy caused by anti-disialosyl ganglioside IgM antibodies, we conclude that determining the anti-ganglioside antibody profile and beginning early treatment should be considered promptly for patients with malignant lymphoma who develop polyneuropathy.

DOI： 10.2169/internalmedicine.54.4451

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Somatic mutation of RUNX1 is implicated in various hematological malignancies, including myelodysplastic syndrome and acute myeloid leukemia (AML), and previous studies using mouse models disclosed its critical roles in hematopoiesis. However, the role of RUNX1 in human hematopoiesis has never been tested in experimental settings. Familial platelet disorder (FPD)/AML is an autosomal dominant disorder caused by germline mutation of RUNX1, marked by thrombocytopenia and propensity to acute leukemia. To investigate the physiological function of RUNX1 in human hematopoiesis and pathophysiology of FPD/AML, we derived induced pluripotent stem cells (iPSCs) from three distinct FPD/AML pedigrees (FPD-iPSCs) and examined their defects in hematopoietic differentiation. By in vitro differentiation assays, FPD-iPSCs were clearly defective in the emergence of hematopoietic progenitors and differentiation of megakaryocytes, and overexpression of wild-type (WT)-RUNX1 reversed most of these phenotypes. We further demonstrated that overexpression of mutant-RUNX1 in WT-iPSCs did not recapitulate the phenotype of FPD-iPSCs, showing that the mutations were of loss-of-function type. Taken together, this study demonstrated that haploinsufficient RUNX1 allele imposed cell-intrinsic defects on hematopoietic differentiation in human experimental settings and revealed differential impacts of RUNX1 dosage on human and murine megakaryopoiesis. FPD-iPSCs will be a useful tool to investigate mutant RUNX1-mediated molecular processes in hematopoiesis and leukemogenesis.

DOI： 10.1038/leu.2014.136

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPANDIDOS PUBL LTD  

Multiple myeloma (MM) is a clonal plasma cell disorder affecting the immune system with various systemic symptoms. MM remains incurable even with high dose chemotherapy using conventional drugs, thus necessitating development of novel therapeutic strategies. Gossypol (Gos) is a natural polyphenolic compound extracted from cotton plants, and has been shown to possess anti-neoplastic activity against various tumors. Recent studies have shown that Gos is an inhibitor for Bcl-2 or Bcl-XL acting as BH3 mimetics that interfere interaction between pro-apoptotic BH3-only proteins and Bcl-2/Bcl-X-L. Since most of the patients with MM overexpress Bcl-2 protein, we considered Gos might be a promising therapeutic agent for MM. We herein show that Gos efficiently induced apoptosis and inhibited proliferation of the OPM2 MM cell line, in a dose- and time-dependent manner. Gos induced activation of caspase-3 and cytochrome c release from mitochondria, showing mitochondrial dysfunction pathway is operational during apoptosis. Further investigation revealed that phosphorylation of Bcl-2 at serine-70 was attenuated by Gos treatment, while protein levels were not affected. In addition, Mcl-1 was downregulated by Gos. Interestingly, phosphorylation of JAK2, STAT3, ERK1/2 and p38MAPK was inhibited by Gos-treatment, indicating that Gos globally suppressed interleukin-6 (IL-6) signals. Moreover, JAK2 inhibition mimicked the effect of Gos in OPM2 cells including Bcl-2 dephosphorylation and Mcl-1 downregulation. These results demonstrated that Gos induces apoptosis in MM cells not only through displacing BH3-only proteins from Bcl-2, but also through inhibiting IL-6 signaling, which leads to Bcl-2 dephosphorylation and Mcl-1 downregulation.

DOI： 10.3892/ijo.2014.2652

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Language：English   Publisher：WILEY-BLACKWELL  

DNA methylation is one of the critical epigenetic modifications regulating various cellular processes such as differentiation or proliferation, and its dysregulation leads to disordered stem cell function or cellular transformation. The ten-eleven translocation (TET) gene family, initially found as a chromosomal translocation partner in leukemia, turned out to be a key enzyme for DNA demethylation. TET genes hydroxylate 5-methylcytosine to 5-hydroxymethylcytosine, which is then converted to unmodified cytosine through multiple mechanisms. Somatic mutations of the TET2 gene were reported in a variety of human hematological malignancies such as leukemia, myelodysplastic syndrome, and malignant lymphoma, suggesting a critical role for TET2 in hematopoiesis. The importance of the TET-mediated cytosine demethylation pathway is also underscored by a recurrent mutation of isocitrate dehydrogenase 1 (IDH1) and IDH2 in hematological malignancies, whose mutation inhibits TET function through a novel oncometabolite, 2-hydroxyglutarate. Studies using mouse models revealed that TET2 is critical for the function of hematopoietic stem cells, and disruption of TET2 results in the expansion of multipotent as well as myeloid progenitors, leading to the accumulation of premalignant clones. In addition to cytosine demethylation, TET proteins are involved in chromatin modifications and other cellular processes through the interaction with O-linked -N-acetylglucosamine transferase. In summary, TET2 is a critical regulator for hematopoietic stem cell homeostasis whose functional impairment leads to hematological malignancies. Future studies will uncover the whole picture of epigenetic and signaling networks wired with TET2, which will help to develop ways to intervene in cellular pathways dysregulated by TET2 mutations.

DOI： 10.1111/cas.12484

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Familial platelet disorder (FPD) with predisposition to acute myelogenous leukaemia (AML) is characterized by platelet defects with a propensity for the development of haematological malignancies. Its molecular pathogenesis is poorly understood, except for the role of germline RUNX1 mutations. Here we show that CDC25C mutations are frequently found in FPD/AML patients (53%). Mutated CDC25C disrupts the G2/M checkpoint and promotes cell cycle progression even in the presence of DNA damage, suggesting a critical role for CDC25C in malignant transformation in FPD/AML. The predicted hierarchical architecture shows that CDC25C mutations define a founding pre-leukaemic clone, followed by stepwise acquisition of subclonal mutations that contribute to leukaemia progression. In three of seven individuals with CDC25C mutations, GATA2 is the target of subsequent mutation. Thus, CDC25C is a novel gene target identified in haematological malignancies. CDC25C is also useful as a clinical biomarker that predicts progression of FPD/AML in the early stage.

DOI： 10.1038/ncomms5770

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Language：English   Publisher：AMER SOC HEMATOLOGY  

DOI： 10.1182/blood-2014-01-552471

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Language：Japanese   Publishing type：Research paper (scientific journal)  

A 62-year-old man with refractory leukemia transformed from myelodysplastic syndrome was placed on hydroxyurea (hydroxycarbamide) at a daily dose of 500 mg. Because of insufficient cytoreductive efficacy, the dose was increased to 1,500 mg five days later. Eight days after the initiation of hydroxyurea, the patient started complaining of chills, fever, and vomiting. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were markedly elevated to 5,098 and 3,880 IU/l from 44 and 59 IU/l in one day, respectively. Tests for hepatitis viruses were all negative. With the discontinuation of hydroxyurea, AST and ALT returned to their former levels within two weeks. A drug-induced lymphocyte stimulation test for hydroxyurea was positive with a stimulating index of 2.0. Hepatic dysfunction has been recognized as one of the side effects of hydroxyurea. However, there have been only a limited number of reports demonstrating drug allergy to have a role in hepatic dysfunction accompanied by fever and gastrointestinal symptoms. The findings of our case strongly suggest that all presentations could be explained by drug allergy. Physicians should be mindful of the potential for acute and severe hepatic dysfunction due to allergic reaction against hydroxyurea.

DOI： 10.11406/rinketsu.55.125

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Publishing type：Research paper (scientific journal)   Publisher：American Society of Hematology  

Abstract

Familial platelet disorder with predisposition to acute myelogenous leukemia (FPD/AML) is an autosomal dominant disorder and is characterized by inherited thrombocytopenia and a lifelong risk of development of hematological malignancies. Although inherited RUNX1 mutation is the cause of thrombocytopenia, additional genetic events may be responsible for the tumor development as only 40 % of FPD/AML patients develop leukemia. Because of the rarity of this disorder, underlying mechanisms for malignant transformation in FPD/AML have not been elucidated. Thus we conducted a nationwide survey in Japan to collect samples and make a diagnosis of patients with familial thrombocytopenia or hematological malignancies. As a result, 56 pedigrees were extracted, and seven pedigrees with RUNX1 mutation were diagnosed as having FPD/AML, in which eight out of 14 patients had developed hematological malignancies. To systematically identify additional genetic alterations, we utilized whole exome sequencing in two patients with FPD/AML who had RUNX1_F303fsX566 mutation and developed MDS (Patient 1) or myelofibrosis (Patient 2) followed by AML. We identified 12 and 10 somatically acquired nonsynonymous mutations in these patients, respectively. Intriguingly, the two patients had common CDC25C mutation at codon 234 (D234G). Further genomic screening of other pedigrees revealed that four out of eight FPD/AML patients who developed hematological malignancy harbored somatic mutations in CDC25C (CDC25C_D234G in three patients and CDC25C_H437N in one patient). Recurrent CDC25C mutation in FPD/AML with subsequent hematological malignancy implies that it forms common genetic foundation of transformation in this disease. CDC25C is a phosphatase that prevents premature mitosis in response to DNA damage at the G2/M checkpoint, while it is constitutively phosphorylated at Ser216 throughout the interphase by c-TAK1. When phosphorylated at Ser216, CDC25C binds to 14-3-3 protein, which sequestrates CDC25C in the cytoplasm and inactivates it. In all of the mutated forms of CDC25C that we found in FPD/AML, their binding capacity with c-TAK1 and 14-3-3 protein was reduced, resulting in decreased phosphorylation status of CDC25C at Ser216. As a consequence, those CDC25C mutants led to enhanced mitosis entry, which was exaggerated by radiation-induced DNA damage. These results demonstrate that CDC25C mutation results in disruption of DNA checkpoint machinery. It is known that FPD/AML-associated RUNX1 mutations evokes DNA damage and induces cell cycle arrest in hematopoietic cells, suggesting that the DNA checkpoint mechanism is activated in the presence of those types of RUNX1 mutation. We found, however, that introduction of CDC25C mutation results in the marked enhancement of mitosis entry in spite of co-expression of RUNX1 mutation in Ba/F3 cells. Thus, premature mitosis by loss of DNA checkpoint mechanisms in the presence of mutated CDC25C may contribute to malignant transformation of RUNX1-mutated cells. Interestingly, analysis of clonal evolution during leukemic transformation revealed that a clone defined by CDC25C mutation was dominant in the early phase of disease progression in both patients, which supports the idea that CDC25C mutation is associated with establishment of the founder clone during the leukemic progression of FPD/AML. In Patient 1, the founder clone with CDC25C mutation acquired FAM22G and COL9A1 (group 1) mutations, followed by occurrence of GATA2 and LPP (group 2) mutations to become a dominant clone in the AML phase, whereas another subclone of the founder defined by CHEK2 and DTX2 (group 3) mutations regressed. Similar hierarchical progression was observed in Patient 2. An additional single cell genomic sequencing of bone marrow cells from Patient 1 in the AML phase revealed that group 1/2 mutations and group 3 mutations were mutually exclusive, which supports our predicted model. Collectively, these results indicate that somatic mutation in CDC25C is a recurrent event in the early phase of leukemic progression of FPD/AML, which induces premature mitosis and genetic instability in hematopoietic cells with germline RUNX1 mutation.

Disclosures:

Usuki: Alexion Pharmaceuticals, Inc.: Speakers Bureau. Kurokawa:Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Consultancy, Research Funding.

DOI： 10.1182/blood.v122.21.739.739

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Oncogenic transformation requires unlimited self-renewal. Currently, it remains unclear whether a normal capacity for self-renewal is required for acquiring an aberrant self-renewal capacity. Our results in a new conditional transgenic mouse showed that a mixed lineage leukemia (MLL) fusion oncogene, MLL-ENL, at an endogenous-like expression level led to leukemic transformation selectively in a restricted subpopulation of hematopoietic stem cells (HSCs) through upregulation of promyelocytic leukemia zinc finger (Plzf). Interestingly, forced expression of Plzf itself immortalized HSCs and myeloid progenitors in vitro without upregulation of Hoxa9/Meis1, which are well-known targets of MLL fusion proteins, whereas its mutant lacking the BTB/POZ domain did not. In contrast, depletion of Plzf suppressed the MLL-fusion-induced leukemic transformation of HSCs in vitro and in vivo. Gene expression analyses of human clinical samples showed that a subtype of PLZF-high MLL-rearranged myeloid leukemia cells was closely associated with the gene expression signature of HSCs. These findings suggested that MLL fusion protein enhances the self-renewal potential of normal HSCs to develop leukemia, in part through a Plzf-driven self-renewal program.

DOI： 10.1182/blood-2012-09-456665

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Roundabout (Robo) family proteins are immunoglobulin-type surface receptors critical for cellular migration and pathway finding of neuronal axons. We have previously shown that Robo4 was specifically expressed in hematopoietic stem and progenitor cells and its high expression correlated with long-term repopulating (LTR) capacity. To reveal the physiological role of Robo4 in hematopoiesis, we examined the effects of Robo4 disruption on the function of hematopoietic stem cells (HSCs) and progenitors. In Robo4-deficient mice, basic hematological parameters including complete blood cell count and differentiation profile were not affected. In contrast to the previous report, HSC/hematopoietic progenitor (HPC) frequencies in the bone marrow (BM) were perfectly normal in Robo4(-/-) mice. Moreover, Robo4(-/-) HSCs were equally competitive as wild-type HSCs in transplantation assays and had normal long-term repopulating (LTR) capacity. Of note, the initial engraftment at 4-weeks after transplantation was slightly impaired by Robo4 ablation, suggesting a marginal defect in BM homing of Robo4(-/-) HSCs. In fact, homing efficiencies of HSCs/HPCs to the BM was significantly impaired in Robo4-deficient mice. On the other hand, granulocyte-colony stimulating factor-induced peripheral mobilization of HSCs was also impaired by Robo4 disruption. Lastly, marrow recovery from myelosuppressive stress was equally efficient in WT- and Robo4-mutant mice. These results clearly indicate that Robo4 plays a role in HSC trafficking such as BM homing and peripheral mobilization, but is not essential in the LTR and self-renewal capacity of HSCs.

DOI： 10.1371/journal.pone.0050849

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Hematopoietic progenitors have been shown to retain plasticity and switch lineages by appropriate stimuli. However, mature blood cells hardly showed such differentiation plasticity. In this paper, we tried to reprogram mature B cells into eiythroid lineage by expressing various hematopoietic transcription factors. Among various factors, GATA-1, SCL together with CCAAT/enhancer binding protein (C/EBP) alpha turned out to be a minimal set of factors that efficiently reprogrammed terminally differentiated mature B cells into erythroid lineage, as evidenced by colony forming assays and erythroid-specific gene expressions. This study sets an avenue to generate autologous erythrocytes from peripheral B cells. (C) 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

DOI： 10.1016/j.febslet.2012.08.019

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DOI： 10.11406/rinketsu.53.219

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Other Link： http://search.jamas.or.jp/link/ui/2012164381

Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Somatic mutation of ten-eleven translocation 2 (TET2) gene is frequently found in human myeloid malignancies. Recent reports showed that loss of Tet2 led to pleiotropic hematopoietic abnormalities including increased competitive repopulating capacity of bone marrow (BM) HSCs and myeloid transformation. However, precise impact of Tet2 loss on the function of fetal liver (FL) HSCs has not been examined. Here we show that disruption of Tet2 results in the expansion of Lin(-)Sca-1(+)c-Kit(+) (LSK) cells in FL. Furthermore, Tet2 loss led to enhanced self-renewal and long-term repopulating capacity of FL-HSCs in in vivo serial transplantation assay. Disruption of Tet2 in FL also led to altered differentiation of mature blood cells, expansion of common myeloid progenitors and increased resistance for hematopoietic progenitor cells (HPCs) to differentiation stimuli in vitro. These results demonstrate that Tet2 plays a critical role in homeostasis of HSCs and HPCs not only in the BM, but also in FL.

DOI： 10.1038/srep00273

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DOI： 10.11406/rinketsu.52.1677

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Various key cell cycle components, especially G0/G1 regulators, have effects not only on cell proliferation but also on cell differentiation. Cdh1, one of the co-activators that maintain anaphase-promoting complex/cyclosome activity, plays a crucial role in the mitotic phase, but has recently been identified as a G0/G1 regulator, suggesting that the role of Cdh1 in cell differentiation. Here, we generated Cdh1 conditional gene-trap mice to examine Cdh1 functions in adult tissues by overcoming the embryonic lethality of Cdh1 homozygous gene-trap mice. We focused on the hematopoietic system and found that Cdh1-deficient mice exhibited a general decrease in mature lineage progenitor cells and a significant increase in short-term hematopoietic stem cells. This phenomenon became conspicuous by irradiation shortly after Cdh1 downregulation, suggesting that Cdh1 regulates the pool sizes of the hematopoietic stem cells and mature lineage progenitor cells by protecting cells from genotoxic stress. We also found that the irradiation-induced G2/M checkpoint was defective in Cdh1-deficient BM cells, causing the loss of stem/progenitor cells. This is the first report revealing Cdh1 function in

DOI： 10.1111/j.1349-7006.2011.01884.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Various key cell cycle components, especially G0/G1 regulators, have effects not only on cell proliferation but also on cell differentiation. Cdh1, one of the co-activators that maintain anaphase-promoting complex/cyclosome activity, plays a crucial role in the mitotic phase, but has recently been identified as a G0/G1 regulator, suggesting that the role of Cdh1 in cell differentiation. Here, we generated Cdh1 conditional gene-trap mice to examine Cdh1 functions in adult tissues by overcoming the embryonic lethality of Cdh1 homozygous gene-trap mice. We focused on the hematopoietic system and found that Cdh1-deficient mice exhibited a general decrease in mature lineage progenitor cells and a significant increase in short-term hematopoietic stem cells. This phenomenon became conspicuous by irradiation shortly after Cdh1 downregulation, suggesting that Cdh1 regulates the pool sizes of the hematopoietic stem cells and mature lineage progenitor cells by protecting cells from genotoxic stress. We also found that the irradiation-induced G2/M checkpoint was defective in Cdh1-deficient BM cells, causing the loss of stem/progenitor cells. This is the first report revealing Cdh1 function in adult hematopoiesis and showing a role of Cdh1 in a G2/M checkpoint regulation in vivo. (Cancer Sci 2011; 102: 967-974).

DOI： 10.1111/j.1349-7006.2011.01884.x

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Two types of mutations of a transcription factor CCAAT-enhancer binding protein alpha(C/EBP alpha) are found in leukemic cells of 5%-14% of acute myeloid leukemia (AML) patients: N-terminal mutations expressing dominant negative p30 and C-terminal mutations in the basic leucine zipper domain. Our results showed that a mutation of C/EBP alpha in one allele was observed in AML after myelodysplastic syndrome, while the 2 alleles are mutated in de novo AML. Unlike an N-terminal frame-shift mutant (C/EBP alpha-N(m))-transduced cells, a C-terminal mutant (C/EBP alpha-C(m))-transduced cells alone induced AML with leukopenia in mice 4-12 months after bone marrow transplantation. Coexpression of both mutants induced AML with marked leukocytosis with shorter latencies. Interestingly, C/EBP alpha-C(m) collaborated with an Flt3-activating mutant Flt3-ITD in inducing AML. Moreover, C/EBP alpha-C(m) strongly blocked myeloid differentiation of 32Dcl3 cells, suggesting its class II mutation-like role in leukemogenesis. Although C/EBP alpha-C(m) failed to inhibit transcriptional activity of wild-type C/EBP alpha, it suppressed the synergistic effect between C/EBP alpha and PU.1. On the other hand, C/EBP alpha-N(m) inhibited C/EBP alpha activation in the absence of PU.1, despite low expression levels of p30 protein generated by C/EBP alpha-N(m). Thus, 2 types of C/EBP alpha mutations are implicated in leukemogenesis, involving different and cooperating molecular mechanisms. (Blood. 2011;117(1):221-233)

DOI： 10.1182/blood-2010-02-270181

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Language：English   Publisher：Keio University School of Medicine  

Differentiation of hematopoietic cells is a sequential process of cell fate decision originating from hematopoietic stem cells (HSCs), allowing multi- or oligopotent progenitors to commit to certain lineages. HSCs are cells that are able to self-renew and repopulate the marrow for the long term. They first differentiate into multipotent progenitors (MPPs), which give rise to common lymphoid progenitors (CLPs) and common myeloid progenitors (CMPs). CMPs then differentiate into granulocyte monocyte progenitors (GMPs) and megakaryocyte erythroid progenitors (MEPs), which are the precursors of granulocytes/monocytes and erythrocytes/megakaryocytes, respectively. Lineage specification at differentiation branch points is dictated by the activation of lineage-specific transcription factors such as C/EBPα, PU.1, and GATA-1. The role of these transcription factors is generally instructive, and the expression of a single factor can often determine cell fate. Differentiation was long regarded as an irreversible process, and it was believed that somatic cells would not change their fate once they were differentiated. This paradigm was first challenged by the finding that ectopic cytokine signals could change the fate of differentiation, probably through modulating internal transcription networks. Subsequently, we and others showed that virtually all progenitors, including CLPs, CMPs, GMPs, and MEPs, still retain differentiation plasticity, and they can be converted into lineages other than their own by ectopic activation of only a single lineage-specific transcription factor. These findings established a novel paradigm for cellular differentiation and opened up an avenue for artificially manipulating cell fate for clinical use. © 2011 by The Keio Journal of Medicine.

DOI： 10.2302/kjm.60.47

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Regulating transition of hematopoietic stem cells (HSCs) between quiescent and cycling states is critical for maintaining homeostasis of blood cell production. The cycling states of HSCs are regulated by the extracellular factors such as cytokines and extracellular matrix; however, the molecular circuitry for such regulation remains elusive. Here we show that tissue inhibitor of metalloproteinase-3 (TIMP-3), an endogenous regulator of metalloproteinases, stimulates HSC proliferation by recruiting quiescent HSCs into the cell cycle. Myelosuppression induced TIMP-3 in the bone marrow before hematopoietic recovery. Interestingly, TIMP-3 enhanced proliferation of HSCs and promoted expansion of multipotent progenitors, which was achieved by stimulating cell-cycle entry of quiescent HSCs without compensating their long-term repopulating activity. Surprisingly, this effect did not require metalloproteinase inhibitory activity of TIMP-3 and was possibly mediated through a direct inhibition of angiopoietin-1 signaling, a critical mediator for HSC quiescence. Furthermore, bone marrow recovery from myelosuppression was accelerated by over-expression of TIMP-3, and in turn, impaired in TIMP-3-deficient animals. These results suggest that TIMP-3 may act as a molecular cue in response to myelosuppression for recruiting dormant HSCs into active cell cycle and may be clinically useful for facilitating hematopoietic recovery after chemotherapy or ex vivo expansion of HSCs. (Blood. 2010;116(22):4474-4482)

DOI： 10.1182/blood-2010-01-266528

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Writ signaling has been implicated in the self-renewal of hematopoietic stem cells (HSCs). Secreted frizzled-related proteins (SFRPs) are a family of soluble proteins containing a region homologous to a receptor for Writ, Frizzled, and are thought to act as endogenous modulators for Writ signaling. This study examined the role of SFRPs in HSC regulation. Among the four family members, SFRP-1 and SFRP-2 are specifically induced in the bone marrow in response to myelosuppression, and immunostaining revealed that both proteins were expressed in osteoblasts. Interestingly, SFRP-1 reduced the number of multipotent progenitors in in vitro culture of CD34(-)KSL cells, while SFRP-2 did not. Furthermore, SFRP-I compromised the long-term repopulating activity of HSCs, whereas SFRP-2 did not affect or even enhanced it in the same setting. These results indicate that although both SFRP-1 and SFRP-2 act as inhibitors for Writ signaling in vitro, they differentially affect the homeostasis of HSCs. (C) 2009 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2009.09.067

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER TOKYO  

It is now conceivable that leukemogenesis requires two types of mutations, class I and class II mutations. We previously established a mouse bone marrow-derived HF6, an IL-3-dependent cell line, that was immortalized by a class II mutation MLL/SEPT6 and can be fully transformed by class I mutations such as FLT3 mutants. To understand the molecular mechanism of leukemogenesis, particularly progression of myelodysplastic syndrome (MDS) to acute leukemia, we made cDNA libraries from the samples of patients and screened them by expression-cloning to detect class I mutations that render HF6 cells factor-independent. We identified RasGRP4, an activator of Ras, as a candidate for class I mutation from three of six patients (MDS/MPD = 1, MDS-RA = 1, MDS/AML = 2, CMMoL/AML = 1 and AML-M2 = 1). To investigate the potential roles of RasGRP4 in leukemogenesis, we tested its in vivo effect in a mouse bone marrow transplantation (BMT) model. C57BL/6J mice transplanted with RasGRP4-transduced primary bone marrow cells died of T cell leukemia, myeloid leukemia, or myeloid leukemia with T cell leukemia. To further examine if the combination of class I and class II mutations accelerated leukemic transformation, we performed a mouse BMT model in which both AML1 mutant (S291fsX300) and RasGRP4 were transduced into bone marrow cells. The double transduction led to early onset of T cell leukemia but not of AML in the transplanted mice when compared to transduction of RasGRP4 alone. Thus, we have identified RasGRP4 as a gene potentially involved in leukemogenesis and suggest that RasGRP4 cooperates with AML1 mutations in T cell leukemogenesis as a class I mutation.

DOI： 10.1007/s12185-009-0299-0

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Mixed-lineage-leukemia (MLL) fusion oncogenes are closely involved in infant acute leukemia, which is frequently accompanied by mutations or overexpression of FMS-like receptor tyrosine kinase 3 (FLT3). Earlier studies have shown that MLL fusion proteins induced acute leukemia together with another mutation, such as an FLT3 mutant, in mouse models. However, little has hitherto been elucidated regarding the molecular mechanism of the cooperativity in leukemogenesis. Using murine model systems of the MLL-fusion-mediated leukemogenesis leading to oncogenic transformation in vitro and acute leukemia in vivo, this study characterized the molecular network in the cooperative leukemogenesis. This research revealed that MLL fusion proteins cooperated with activation of Ras in vivo, which was substitutable for Raf in vitro, synergistically, but not with activation of signal transducer and activator of transcription 5 (STAT5), to induce acute leukemia in vivo as well as oncogenic transformation in vitro. Furthermore, Hoxa9, one of the MLL-targeted critical molecules, and activation of Ras in vivo, which was replaceable with Raf in vitro, were identified as fundamental components sufficient for mimicking MLL-fusion-mediated leukemogenesis. These findings suggest that the molecular crosstalk between aberrant expression of Hox molecule(s) and activated Raf may have a key role in the MLL-fusion-mediated-leukemogenesis, and may thus help develop the novel molecularly targeted therapy against MLL-related leukemia. © 2009 Macmillan Publishers Limited All rights reserved.

DOI： 10.1038/leu.2009.177

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STAT5 is a critical mediator of a variety of cytokine signaling whose transcriptional activity is regulated by associating with various proteins. During a search for STAT5-interacting proteins, we identified SHD1, a mammalian homologue of yeast gene Sac3, as a potential interacter. SHD1 was localized in the nucleus, and induced by cytokines that activate STAT5, such as erythropoietin, interleukin-2 (IL-2), or IL-3. SHD1 interacted specifically with STAT5A and STAT5B, and interestingly, it specifically repressed STAT5-dependent transcription in vitro without affecting the stability or phosphorylation of STAT5 protein. Gene disruption study revealed that T, B, or bone marrow cells from mice lacking SHD1 were hyperresponsive to T-cell -receptor engagement, or stimulation with various STAT5-activating cytokines. These results suggest that SHD1 is a novel cytokine-inducible negative feedback regulator of STAT5. (Blood. 2009;113:1027-1036)

DOI： 10.1182/blood-2008-01-133405

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ALPHAMED PRESS  

Roundabout (Robo) family proteins are immunoglobulin-type cell surface receptors that are expressed predominantly in the nervous system. The fourth member of this family, Robo4, is distinct from the other family members in that it is expressed specifically in endothelial cells. In this study, we examined the expression of Robo4 in hematopoietic stem cells (HSCs) and its possible role in HSC regulation. Robo4 mRNA was specifically expressed in murine HSCs and the immature progenitor cell fraction but not in lineage-positive cells or differentiated progenitors. Moreover, flow cytometry showed a correlation between higher expression of Robo4 and immature phenotypes of hematopoietic cells. Robo4(high) hematopoietic stem/progenitor cells presented higher clonogenic activity or long-term repopulating activity by colony assays or transplantation assays, respectively. A ligand for Robo4, Slit2, is specifically expressed in bone marrow stromal cells, and its expression was induced in osteoblasts in response to myelosuppressive stress. Interestingly, overexpression of Robo4 or Slit2 in HSCs resulted in their decreased residence in the c-Kit(+)Sea-1(+)Lineage(-)-side population fraction. These results indicate that Robo4 is expressed in HSCs, and Robo4/Slit2 signaling may play a role in HSC homeostasis in the bone marrow niche. STEM CELLS 2009; 27: 183-190

DOI： 10.1634/stemcells.2008-0292

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CCAAT/enhancer binding proteins (C/EBPs) have an important function in granulocytic differentiation, and are also involved in the leukemogenesis of acute myeloid leukemia (AML). Their involvement in myelomonocytic leukemia, however, is still unclear. Therefore, the expression and function of C/EBPs in myelomonocytic cells with MLL-fusion genes were investigated. Retinoic acid (RA) induced monocytic differentiation in the myelomonocytic cell lines with MLL-fusion genes, THP-1, MOLM-14 and HF-6 cells, accompanied by monocytic differentiation with the upregulation of C/EBP alpha and C/EBP epsilon. Monocytic differentiation by RA treatment was confirmed in primary AML cells using a clonogenic assay. When the activity of C/EBP alpha or C/EBP epsilon was introduced into HF-6 cells, their cellular growth was arrested through differentiation into monocytes with the concomitant marked downregulation of Myc. Cebpe mRNA was upregulated by the induction of C/EBP alpha-ER, but not vice versa, thus suggesting that C/EBP epsilon may have an important function in the differentiation process. Introduction of Myc isoforms into HF-6 cells partially antagonized the C/EBP alpha effects. These findings suggest that the ectopic expression of C/EBP epsilon, as well as C/EBP alpha, can induce the monocytic differentiation of myelomonocytic leukemic cells with MLL-fusion gene through the downregulation of Myc, thus providing insight into the development of novel therapeutic approaches.

DOI： 10.1038/onc.2008.285

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Myelodysplastic syndrome (MDS) is a hematopoietic stem-cell disorder characterized by trillneage dysplasia and susceptibility to acute myelogenous leukemia (AML). Analysis of molecular basis of MDS has been hampered by the heterogeneity of the disease. Recently, mutations of the transcription factor AML1/RUNX1 have been identified in 15% to 40% of MDS-refractory anemia with excess of blasts (RAEB) and MDS/AML. We performed mouse bone marrow transplantation (BMT) using bone marrow cells transduced with the AML1 mutants. Most mice developed MDS and MDS/AML-like symptoms within 4 to 13 months after BMT. Interestingly, among integration sites identified,Evil seemed to collaborate with an AML1 mutant harboring a point mutation in the Runt homology domain (D171N) to induce MDS/AML with an identical phenotype characterized by marked hepatosplenomegaly, myeloid dysplasia, leukocytosis, and biphenotypic surface markers. Collaboration between AML1-D171N and Evil was confirmed by a BMT model where coexpression of AML1-D171N and Evil induced acute leukemia of the same phenotype with much shorter latencies. On the other hand, a C-terminal truncated AML1 mutant (S291fsX300) induced pancytopenia with erythroid dysplasia in transplanted mice, followed by progression to MDS-RAEB or MDS/AML. Thus, we have developed a useful mouse model of MDS/AML that should help in the understanding of the molecular basis of MDS and the progression of MDS to overt leukemia.

DOI： 10.1182/blood-2007-01-068346

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Placental tissue draws great interest as a source of cells for regenerative medicine because of the phenotypic plasticity of many of the cell types isolated from this tissue. Furthermore, placenta, which is involved in maintaining fetal tolerance, contains cells that display immunomodulatory properties. These two features could prove useful for future cell therapy-based clinical applications. Placental tissue is readily available and easily procured without invasive procedures, and its use does not elicit ethical debate. Numerous reports describing stem cells from different parts of the placenta, using nearly as numerous isolation and characterization procedures, have been published. Considering the complexity of the placenta, an urgent need exists to define, as clearly as possible, the region of origin and methods of isolation of cells derived from this tissue. On March 23-24, 2007, the first international Workshop on Placenta Derived Stem Cells was held in Brescia, Italy. Most of the research published in this area focuses on mesenchymal stromal cells isolated from various parts of the placenta or epithelial cells isolated from amniotic membrane. The aim of this review is to summarize and provide the state of the art of research in this field, addressing aspects such as cell isolation protocols and characteristics of these cells, as well as providing preliminary indications of the possibilities for use of these cells in future clinical applications.

DOI： 10.1634/stemcells.2007-0594

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We have analyzed leukocyte mono-Ig-like receptor 5 (LMIR5) as an activating receptor among paired LMIRs. Mouse LMIR5 (mLMIR5) is expressed in myeloid cells such as mast cells, granulocytes, macrophages, and dendritic cells. Cross-linking of transduced mLMIR5 in bone marrow-derived mast cells (BMMCs) caused activation events, including cytokine production, cell survival, degranulation, and adhesion to the extracellular matrix. mLMIR5 associated with DAP12 and to a lesser extent with DAP10, and mLMIR5-mediated functions of BMMCs were strongly inhibited by DAP12 deficiency. Importantly, cross-linking of endogenous mLMIR5 induced Syk-dependent activation of fetal liver-derived mast cells. Unlike mLMIR5, cross-linking of human LMIR5 (hLMIR5) induced cytokine production of BMMCs even in the absence of both DAP12 and DAP10, suggesting the existence of unidentified adaptors. Interestingly, hLMIR5 possessed a tyrosine residue (Y188) in the cytoplasmic region. Signaling via Y188 phosphorylation played a predominant role in hLMIR5-mediated cytokine production in DAP12-deficient, but not wild-type BMMCs. In addition, experiments using DAP10/DAP12 double-deficient BMMCs suggested the existence of Y188 phoshorylation-dependent and -independent signals from unidentified adaptors. Collectively, although both mouse and human LMIR5 play activatory roles in innate immunity cells, the functions of LMIR5 were differentially regulated in mouse versus human cells.

DOI： 10.1182/blood-2007-04-085787

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Previous studies using loss-of-function mutants revealed that CCAAT/enhancer-binding protein alpha (C/EBP alpha) and PU.1 are potential regulators for hematopoietic stem cells (HSCs). To gain further insight into the HSC regulation by C/EBP alpha or PU.1, we used transgenic mice expressing conditional forms of these transcription factors to examine whether their activation alone is sufficient for modulating HSC functions. The activation of C/EBP alpha or PU.1 in HSCs in vitro or in vivo led to their suppression of growth, decreased mixed colony formation, and impaired competitive repopulating activities because of their defective self-renewal. These effects were more prominently observed when C/EBP alpha was activated, and the differentiation capacity to megakaryocytic lineage was selectively impaired upon C/EBP alpha activation. Unexpectedly, the expression of Bmi-1 and HoxB4, well-known regulators for self-renewal of HSCs, was not affected by the activation of C/EBP alpha or PU.1, suggesting that they regulate HSC function through an as yet unknown mechanism. Our data suggest that the activation of C/EBP alpha or PU.1 is sufficient to repress stem cell capacities in HSCs, and their fine-tuned regulation is critical for HSC homeostasis. STEM CELLS 2008;26:3172-3181

DOI： 10.1634/stemcells.2008-0320

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DOI： 10.1038/sj.leu.2404883

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The leukocyte mono-Ig-like receptor (LMIR) belongs to a new family of paired immunoreceptors. In this study, we analyzed activating receptor LMIR4/CLM-5 as a counterpart of inhibitory receptor LMIR3/CLM-1. LMIR4 is expressed in myeloid cells, including granulocytes, macrophages, and mast cells, whereas LMIR3 is more broadly expressed. The association of LMIR4 with Fc receptor-gamma among immunoreceptor tyrosine-based activation motif-bearing molecules was indispensable for LMIR4-mediated functions of bone marrow-derived mast cells, but dispensable for its surface expression. Cross-linking of LMIR4 led to Lyn- and Syk-dependent activation of bone marrow-derived mast cells, resulting in cytokine production and degranulation, whereas that of LMIR3 did not. The triggering of LMIR4 and TLR4 synergistically caused robust cytokine production in accordance with enhanced activation of ERK, whereas the co-ligation of LMIR4 and LMIR3 dramatically abrogated cytokine production. Notably, intraperitoneal administration of lipopolysaccharide strikingly up-regulated LMIR3 and down-regulated LMIR4, whereas that of granulocyte colony-stimulating factor up-regulated both LMIR3 and LMIR4 in granulocytes. Cross-linking of LMIR4 in bone marrow granulocytes also resulted in their activation, which was enhanced by lipopolysaccharide. Collectively, these results suggest that the innate immune system is at least in part regulated by the qualitative and quantitative balance of the paired receptors LMIR3 and LMIR4.

DOI： 10.1074/jbc.M701100200

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TAT transcription factors are tyrosine phosphorylated upon cytokine stimulation and enter the nucleus to activate target genes. We show that Rac1 and a GTPase-activating protein, MgcRacGAP, bind directly to p-STAT5A and are required to promote its nuclear translocation. Using permeabilized cells, we find that nuclear translocation of purified p-STAT5A is dependent on the addition of GTP-bound Rac1, MgcRacGAP, importin alpha, and importin beta. p-STAT3 also enters the nucleus via this transport machinery, and mutant STATs lacking the MgcRacGAP binding site do not enter the nucleus even after phosphorylation. We conclude that GTP-bound Rac1 and MgcRacGAP function as a nuclear transport chaperone for activated STATs.

DOI： 10.1083/jcb.200604073

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

The interleukin 21 (IL-21) receptor is expressed on T-cells, B-cells, and natural killer cells, and IL-21 is critical for regulating immunoglobulin production in vivo in cooperation with IL-4. So far, however, little is known about a role for IL-21 outside the immune system. We investigated the effect of IL-21 on hematopoiesis in vivo by using the hydrodynamics gene-delivery method. Overexpression of IL-21 increases Sca-1(+) cells in the periphery and spleen. It also increases the numbers of c-Kit(+), Sca-1(+), and lineage(-/low) (KSL) cells and colony-forming units-granulocyte-macrophage (CFU-GM) in the spleen, indicating the expansion of hematopoietic progenitor cells. We found that even in RAG2(-/-) mice, which lack mature T-cells and B-cells, IL-21 induced an increase in KSL cells and CFU-GM in the spleen. These results demonstrate that IL-21 can induce the expansion of hematopoietic progenitor cells in vivo, even in the absence of mature T-cells and B-cells.

DOI： 10.1532/IJH97.06036

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CARDEN JENNINGS PUBL CO LTD  

Internal tandem duplication of FLT3 tyrosine kinase (FLT3-ITD) is the most prevalent mutation found in acute myelogenous leukemia (AML), having been identified in 20% to 30% of all AML patients. We have previously shown that FLT3-ITD signals mainly through the signal transducer and activator of transcription 5 (STAT5) pathway and have suggested the possible involvement of Tyk2 in STAT5 activation by FLT3-ITD. The present study addressed the role of Tyk2 in FLT3-ITD signaling in a murine bone marrow transplantation (BMT) model. Transplantation of wild-type bone marrow cells transduced with the FLT3-ITD gene induced lethal myeloproliferative disease (MPD) in the recipient mice at a median latency of 89 days. Interestingly, some mice presented the proliferation of B- or T-lymphoid blasts in various organs, a presentation that resembled acute lymphoblastic leukemia (ALL). Mice that received Tyk2-deficient bone marrow cells transduced with FLT3-ITD developed lethal MPD with a disease latency (median, 100 days) and pathologic picture similar to those of mice that received wild-type bone marrow cells. These results indicate that (1) Tyk2 is not essential for MPD induction by FLT3-ITD and (2) FLT3-ITD by itself can induce ALL in a murine BMT model.

DOI： 10.1532/IJH97.06016

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

CCAAT/enhancer-binding protein (C/EBP) a is a critical regulator for early myeloid differentiation. Although C/EBP alpha has been shown to convert B cells into myeloid lineage, precise roles of C/EBP alpha in various hematopoietic progenitors and stem cells still remain obscure. To examine the consequence of C/EBP alpha activation in various progenitors and to address the underlying mechanism of lineage conversion in detail, we established transgenic mice expressing a conditional form of C/EBP alpha. Using these mice, we show that megakaryocyte/erythroid progenitors (MEPs) and common lymphoid progenitors (CLPs) could be redirected to functional macrophages in vitro by a short-term activation of C/EBP alpha, and the conversion occurred clonally through biphenotypic intermediate cells. Moreover, in vivo activation of C/EBP alpha in mice led to the increase of mature granulocytes and myeloid progenitors with a concomitant decrease of hematopoietic stem cells and nonmyeloid progenitors. Our study reveals that C/EBP alpha can activate the latent myeloid differentiation program of MEP and CLP and shows that its global activation affects multilineage homeostasis in vivo.

DOI： 10.1038/sj.emboj.7601199

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

CCAAT/enhancer-binding protein epsilon (C/EBP epsilon) plays a critical role in terminal myeloid differentiation. Differentiation is an integrated process of cell cycle arrest, morphological change, functional maturation, and apoptosis. However, the molecular networks underlying these events in C/EBP epsilon-induced differentiation remain poorly understood. To reveal these mechanisms, we performed a detailed molecular analysis of C/EBP epsilon-induced differentiation using an inducible form of C/EBP epsilon. The activation of C/EBP epsilon induced growth arrest, morphological differentiation, the expression of CD11b and secondary granule proteins, and apoptosis in myeloid cell lines. Unlike C/EBP alpha, C/EBP epsilon dramatically up-regulated p27 with a concomitant down-regulation of cdk4/6 and cyclin D2/A/E. Moreover, the anti-apoptotic proteins Bcl-2 and Bcl-x were down-regulated, whereas pro-apoptotic protein Bax remained unchanged. Using a variety of mutants, we revealed that these events were all regulated by the N-terminal activation domain of C/EBP epsilon. Interestingly, some of the differentiation processes such as the induction of secondary granule protein genes were clearly inhibited by c-Myc; however, inhibition of apoptosis by Bcl-x did not affect the entire differentiation processes. These data indicate the N terminus of C/EBP epsilon to be solely responsible for most aspects of myeloid differentiation, and these events were differentially affected by c-Myc.

DOI： 10.1074/jbc.M600575200

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Immune suppressor factor (ISF) is a subunit of the vacuolar ATPase proton pump. We earlier identified a short form of ISF (ShIF) as a stroma-derived factor that supports cytokine-independent growth of mutant Ba/F3 cells. Here, we report that ISF/ShIF supports selfrenewal and expansion of primary hematopoietic stem cells (HSCs). Co-culture of murine bone marrow cells with a stromal cell line overexpressing ISF or ShIF (MS10/ISF or MS10/ShIF) not only enhanced their colony-forming activity and the numbers of long-term culture initiating cells, but also maintained the competitive repopulating activity of HSC. This stem cell supporting activity depended on the proton-transfer function of ISF/ShIF. Gene expression analysis of ISF/ShIF-transfected cell lines revealed down-regulation of secreted frizzled-related protein-1 and tissue inhibitor of metalloprotemase-3, and the restoration of their expressions in MSIO/ISF cells partially reversed its enhanced LTC-IC supporting activity to a normal level. These results suggest that ISF/ShIF confers stromal cells with enhanced supporting activities for HSCs by modulating Writ-activity and the extracellular matrix. (c) 2005 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2005.11.146

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC IMMUNOLOGISTS  

Integrin alpha(IIb), a well-known marker of megakaryocyte-platelet lineage, has been recently recognized on hemopoietic progenitors. We now demonstrate that integrin alpha(IIb)beta(3) is highly expressed on mouse and human mast cells including mouse bone marrow-derived mast cells, peritoneal mast cells, and human cord blood-derived mast cells, and that its binding to extracellular matrix proteins leads to enhancement of biological functions of mast cells in concert with various stimuli. With exposure to various stimuli, including cross-linking of Fc epsilon RI and stem cell factor, mast cells adhered to extracellular matrix proteins such as fibrinogen and von Willebrand factor in an integrin alpha(IIb)beta(3)-dependent manner. In addition, the binding of mast cells to fibrinogen enhanced proliferation, cytokine production, and migration and induced uptake of soluble fibrinogen in response to stem cell factor stimulation, implicating integrin alpha(IIb)beta(3) in a variety of mast cell functions. In conclusion, mouse and human mast cells express functional integrin alpha(IIb)beta(3).

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Septins are evolutionarily conserved GTP-binding proteins that can heteropolymerize into filaments. Recent studies have revealed that septins are involved in not only diverse normal cellular processes but also the pathogenesis of various diseases, including cancer. SEPT6 is ubiquitously expressed in tissues and one of the fusion partner genes of MLL in the 11q23 translocations implicated in acute leukemia. However, the roles of this septin in vivo remain elusive. We have developed Sept6-deficient mice that exhibited neither gross abnormalities, changes in cytokinesis, nor spontaneous malignancy. Sept6 deficiency did not cause any quantitative changes in any of the septins evaluated in this study, nor did it cause any additional changes in the Sept4-deficient mice. Even the depletion of Sept11, a close homolog of Sept6, did not affect the Sept6-null cells in vitro, thus implying a high degree of redundancy in the septin system. Furthermore, a loss of Sept6 did not alter the phenotype of myeloproliferative disease induced by MLL-SEPT6, thus suggesting that Sept6 does not function as a tumor suppressor. To our knowledge, this is the first report demonstrating that a disruption of the translocation partner gene of MLL in 11q23 translocation does not contribute to leukemogenesis by the MLL fusion gene.

DOI： 10.1128/MCB.25.24.10965-10978.2005

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AF5q31 (also called MCEF) was identified by its involvement in chromosomal translocation with the gene MLL (mixed lineage leukemia), which is associated with infant acute lymphoblastic leukemia. Several potential roles have been proposed for AF5q31 and other family genes, but the specific requirements of AF5q31 during development remain unclear. Here, we show that AF5q31 is essential for spermatogenesis. Although most AF5q31-deficient mice died in utero and neonatally with impaired embryonic development and shrunken alveoli, respectively, 13% of AF5q31-deficient mice thrived as wild-type mice did. However, the male mice were sterile with azoospermia. Histological examinations revealed the arrest of germ cell development at the stage of spermiogenesis, and virtually no spermatozoa were seen in the epididymis. AF5q31 was found to be preferentially expressed in Sertoli cells. Furthermore, mutant mice displayed severely impaired expression of protamine 1, protamine 2, and transition protein 2, which are indispensable to compact the haploid genome within the sperm head, and an increase of apoptotic cells in seminiferous tubules. Thus, AF5q31 seems to function as a transcriptional regulator in testicular somatic cells and is essential for male germ cell differentiation and survival. These results may have clinical implications in the understanding of human male infertility.

DOI： 10.1128/MCB.25.15.6834-6845.2005

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC CLINICAL INVESTIGATION INC  

The mechanisms by which mixed-lineage leukemia (MLL) fusion products resulting from in utero translocations in 11q23 contribute to leukemogenesis and infant acute leukemia remain elusive. It is still controversial whether the MLL fusion protein is sufficient to induce acute leukemia without additional genetic alterations, although carcinogenesis in general is known to result from more than I genetic disorder accumulating during a lifetime. Here we demonstrate that the fusion partner-mediated homo-oligomerization of MLL-SEPT6 is essential to immortalize hematopoietic progenitors in vitro. MLL-SEPT6 induced myeloproliferative disease with long latency in mice, but not acute leukemia, implying that secondary genotoxic events are required to develop leukemia. We developed in vitro and in vivo model systems of leukemogenesis by MLL fusion proteins, where activated FMS-like receptor tyrosine kinase 3 (FLT3) together with MLL-SEPT6 not only transformed hematopoietic progenitors in vitro but also induced acute biphenotypic or myeloid leukemia with short latency in vivo. In these systems, MLL-ENL, another type of the fusion product that seems to act as a monomer, also induced the transformation in vitro and leukemogenesis in vivo in concert with activated FLT3. These findings show direct evidence for a multistep leukemogenesis mediated by MLL fusion proteins and may be applicable to development of direct MLL fusion-targeted therapy.

DOI： 10.1172/JCI200522725

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

The Janus kinase (Jak)-Stat pathway plays an essential role in cytokine signaling. Granulocyte colony-stimulating factor (G-CSF) promotes granulopoiesis and granulocytic differentiation, and Stat3 is the principle Stat protein activated by G-CSF. Upon treatment with G-CSF, the interleukin-3-dependent cell line 32D clone 3(32Dcl3) differentiates into neutrophils, and 32Dcl3 cells expressing dominant-negative Stat3 (32Dcl3/ DNStat3) proliferate in G-CSF without differentiation. Gene expression profile and quantitative PCR analysis of G-CSF-stimulated cell lines revealed that the expression of C/EBP alpha was up-regulated by the activation of Stat3. In addition, activated Stat3 bound to CCAAT/enhancer-binding protein (C/EBP)alpha, leading to the enhancement of the transcription activity of C/EBP alpha. Conditional expression of C/EBP alpha in 32Dcl3/ DNStat3 cells after G-CSF stimulation abolishes the G-CSF-dependent cell proliferation and induces granulocytic differentiation. Although granulocyte-specific genes, such as the G-CSF receptor, lysozyme M, and neutrophil gelatinase-associated lipocalin precursor (NGAL) are regulated by Stat3, only NGAL was induced by the restoration of C/EBP alpha after stimulation with G-CSF in 32Dcl3/ DNStat3 cells. These results show that one of the major roles of Stat3 in the G-CSF signaling pathway is to augment the function of C/EBP alpha, which is essential for myeloid differentiation. Additionally, cooperation of C/EBP alpha with other Stat3-activated proteins are required for the induction of some G-CSF responsive genes including lysozyme M and the G-CSF receptor.

DOI： 10.1074/jbc.M408442200

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We previously identified a guanosine triphosphatase (GTPase)-activating protein (GAP) (m) under bar ale (g) under bar erm (c) under bar ell Rac GAP (MgcRacGAP) that enhanced interleukin-6 (IL-6)-induced macrophage differentiation of murine M1 leukemia cells. Later, MgcRacGAP was found to play crucial roles in cell division. However, how MgcRacGAP enhanced IL-6-induced differentiation remained elusive. Here we show that MgcRacGAP enhances IL-6-induced differentiation through enhancement of signal transducer and activator of transcription-3 (STAT3) activation. MgcRacGAP, Rac, and STAT3 formed a complex in IL-6-stimulated M1 cells, where MgcRacGAP interacted with Rac1 and STAT3 through its cysteine-rich domain and GAP domain. In reporter assays, the wild-type MgcRacGAP enhanced transcriptional activation of STAT3 while a GAP-domain deletion mutant (DeltaGAP) did not significantly enhance it, suggesting that the GAP domain was required for enhancement of STAT3-dependent transcription. Intriguingly, M1 cells expressing DeltaGAP had no effect on the differentiation signal of IL-6, while forced expression of MgcRacGAP rendered M1 cells hyper-responsive to the IL-6-induced differentiation. Moreover, knockdown of MgcRacGAP by RNA interference profoundly suppressed STAT3 activation, implicating MgcRacGAP in the STAT3-dependent transcription. All together, our data not only reveal an important role for MgcRacGAP in STAT3 activation, but also demonstrate that MgcRacGAP regulates IL-6-induced cellular differentiation in which STAT3 plays a pivotal role. (C) 2004 by The American Society of Hematology.

DOI： 10.1182/blood-2004-03-1066

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Retinolds are potent inducers of cell cycle arrest and differentiation of numerous cell types, notably granulocytes. However the mechanisms by which retinoids mediate cell cycle arrest during differentiation remain unclear. We have used myeloid differentiation to characterize the molecular pathways that couple cell cycle withdrawal to terminal differentiation. Using primary cells from mice deficient for either the cyclin-dependent kinase inhibitor (CDKi) p27Kip1, the Myc antagonist Mad1, or both Madl and p27(Kip1), we observed that signals mediated through reti-sponse to RARalpha specifically requires Mad1 and p27(Kip1) and that Mad1 is transcriptionally activated by CCAAT/ enhancer-binding protein E (C/EBPE). Moreover, these data demonstrate selectivity among the RARs for cell cycle arrest pathways and provide a direct mechanism to link differentiation induction and regulation of the Myc antagonist Mad1. (C) 2004 by The American Society of Hematology.

DOI： 10.1182/blood-2003-07-2391

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ALPHAMED PRESS  

Mesenchymal stem/progenitor cells (MSCs) are widely distributed in a variety of tissues in the adult human body (e.g., bone marrow [BM], kidney, lung, and liver). These cells are also present in the fetal environment (e.g., blood, liver, BM, and kidney). However, MSCs are a rare population in these tissues. Here we tried to identify cells with MSC-like potency in human placenta. We isolated adherent cells from trypsin-digested term placentas and established two clones by limiting dilution. We examined these cells for morphology, surface markers, gene expression patterns, and differentiation potential and found that they expressed several stem cell markers, hematopoietic/endothelial cell-related genes, and organ-specific genes, as determined by reverse transcription-polymerase chain reaction and fluorescence-activated cell sorter analysis. They also showed osteogenic and adipogenic differentiation potentials under appropriate conditions. We suggest that placenta-derived cells have multilineage differentiation potential similar to MSCs in terms of morphology, cell-surface antigen expression, and gene expression patterns. The placenta may prove to be a useful source of MSCs.

DOI： 10.1634/stemcells.22-5-649

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL MUNKSGAARD  

Many hematopoietic cells undergo apoptosis when deprived of specific cytokines. Lipocalin 24p3, reported to be induced in hematopoietic cells by interleukin 3 (IL-3) depletion, induces hematopoietic cell apoptosis despite the presence of IL-3. As granulocyte colony stimulating factor (G-CSF) depletion also induces the apoptosis of G-CSF-dependent cell line cells, we examined the effect of 24p3 on the apoptotic function induced by G-CSF depletion. 24p3 was induced by the depletion of IL-3, but not G-CSF, in cytokine-dependent cell lines. Although 24p3 suppressed growth induced by IL-3, it did not influence G-CSF-dependent cell growth. These observations show that 24p3 is not involved in the G-CSF withdrawal-induced apoptosis, although it is essential in IL-3 withdrawal-induced apoptosis.

DOI： 10.1046/j.0902-4441.2003.00160.x

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Language：English   Publisher：ELSEVIER SCIENCE INC  

Most of the human genome has now been sequenced and about 30,000 potential open reading frames have been identified, indicating that we use these 30,000 genes to functionally organize our biologic activities. However, functions of many genes are still unknown despite intensive efforts using bioinformatics as well as transgenic and knockout mice. Retrovirus-mediated gene transfer is a powerful tool that can be used to understand gene functions. We have developed a variety of retrovirus vectors and efficient packaging cell lines that have facilitated the development of efficient functional expression cloning methods. In this review, we describe retrovirus-mediated strategies used for investigation of gene functions and function-based screening strategies. (C) 2003 International Society for Experimental Hematology. Published by Elsevier Inc.

DOI： 10.1016/j.exphem.2003.07.005

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We have identified and characterized two mouse cDNAs in a mouse antigen-stimulated bone marrow-derived mast cell cDNA library. both of which encode type I transmembrane proteins. The genes were closely mapped in the distal region of mouse chromosome I I and expressed not only in mast cells but also widely in leukocytes. The extracellular domains of their encoded proteins contain a single variable immunoglobulin (Ig) motif sharing about 90% identity with amino acids, showing that they comprise a pair of molecules and belong to the Ig superfamily. We named these molecules leukocyte mono-Ig-like receptor1 and 2 (LMIR1 and 2). The intracellular domain of LMIR1 contains several immunoreceptor tyrosine-based inhibition motifs (ITIMs). When cross-linked, the intracellular domain was tyrosine phosphorylated and capable of recruiting tyrosine phosphatases, SHP-1 and SHP-2 and inositol polyphosphate 5-phosphatase, SHIP. LMIR2, on the other hand, contains a short cytoplasmic tail and a characteristic transmembrane domain carrying two positively charged amino acids associated with three kinds of immunoreceptor tyrosine-based activation motif (ITAM)-bearing molecules, DAP10, DAP12, and FcRgamma. These findings suggest that a new pair of ITIM/ITAM -bearing receptors, LMIR1 and 2, regulate mast cell-mediated inflammatory responses through yet to be defined ligand(s). (C) 2003 Elsevier Inc. All rights reserved.

DOI： 10.1016/S0006-291X(03)01245-2

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

The receptor tyrosine kinase FLT3 is constitutively activated by an internal tandem duplication (ITD) mutation within the juxtamembrane domain in 20 - 30% of patients with acute myeloid leukemia. In this study, we identified GTP-14564 as a specific kinase inhibitor for ITD-FLT3 and investigated the molecular basis of its specificity. GTP-14564 inhibited the growth of interleukin-3-independent Ba/F3 expressing ITD-FLT3 at 1 muM, whereas a 30-fold higher concentration of GTP-14564 was required to inhibit FLT3 ligand-dependent growth of Ba/F3 expressing wild type FLT3 (wt-FLT3). However, this inhibitor suppressed the kinase activities of wt-FLT3 and ITD-FLT3 equally, suggesting that the signaling pathways for proliferation differ between wt-FLT3 and ITD-FLT3. Analysis of downstream targets of FLT3 using GTP-14564 revealed STAT5 activation to be essential for growth signaling of ITD-FLT3. In contrast, wt-FLT3 appeared to mainly use the MAPK pathway rather than the STAT5 pathway to transmit a proliferative signal. Further analysis demonstrated that the first two tyrosines in an ITD were critical for STAT5 activation and growth induction but that all of the tyrosines in the juxtamembrane region were dispensable in terms of the proliferation signals of wt-FLT3. These results indicate that an ITD mutation in FLT3 elicits an aberrant STAT5 activation that results in increased sensitivity to GTP-14564. Thus, FLT3-targeted inhibition is an attractive approach, with the potential for selective cytotoxicity, to the treatment of ITD-FLT3-positive acute myeloid leukemia.

DOI： 10.1074/jbc.M210405200

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Phosphoinositide 3-kinases (PI3Ks), a family of lipid kinases comprising 3 classes with multiple isoforms, have been shown to participate in different phases of platelet signaling. To investigate the roles that enzymes play in platelet function in vivo and determine which isoforms are important for particular signaling events, we analyzed platelet function of gene knockout mice deficient in the p85 regulatory subunit of heterodimeric class IA PI3K. The kinase activity of p85alpha-/- platelets was only 5% of the activity of platelets from wild-type littermates. Platelet aggregation induced by adenosine diphosphate (ADP), thrombin, U46619, phorbol 12-myristate 13-acetate (PMA), or botrocetin was not defective in p85alpha-/- mice, compared with wild-type animals. In contrast, aggregation induced by collagen and collagen-related peptide (CRP) was partially but readily impaired in p85alpha-/- mice. Both P-selectin expression and fibrinogen binding in response to CRP were also decreased to a similar extent in p85alpha-/- platelets. Platelets from p85alpha-/- mice appeared to spread poorly over a CRP-coated surface with intact filopodial protrusions. Significant attenuation of CRP-induced tyrosine phosphorylation in known PI3K effectors such as Btk, Tec, PKB/Akt, and phospholipase Cgamma2 were observed with p85alpha-/- platelets, whereas no alteration was noted in upstream molecules of Syk, LAT, and SLP-76. Considered as a whole, these results provide the first genetic evidence that P13K p85alpha plays a significant role in platelet function, almost exclusively in the glycoprotein (GP) VI/Fc receptor gamma chain complex-mediated signaling pathway. (C) 2003 by The American Society of Hematology.

DOI： 10.1182/blood-2002-11-3327

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Dorsoventral patterning depends on the local concentrations of the morphogens. Twisted gastrulation (TSG) regulates the extracellular availability of a mesoderm inducer, bone morphogenetic protein 4 (BMP-4). However, TSG function in vivo is still unclear. We isolated a TSG cDNA as a secreted molecule from the mouse aorta-gonad-mesonephros region. Here we show that TSG-deficient mice were born healthy, but more than half of the neonatal pups showed severe growth retardation shortly after birth and displayed dwarfism with delayed endochondral ossification and lymphopenia, followed by death within a month. TSG-deficient thymus was atrophic, and phosphorylation of SMAD1 was augmented in the thymocytes, suggesting enhanced BMP-4 signaling in the thymus. Since BMP-4 promotes skeletogenesis and inhibits thymus development, our findings suggest that TSG acts as both a BMP-4 agonist in skeletogenesis and a BMP-4 antagonist in T-cell development. Although lymphopenia in TSG-deficient mice would partly be ascribed to systemic effects of runtiness and wasting, our findings may also provide a clue for understanding the pathogenesis of human dwarfism with combined immunodeficiency.

DOI： 10.1128/MCB.23.8.2969-2980.2003

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CCAAT/enhancer binding proteins (C/ EBPs) are a family of factors that regulate cell growth and differentiation. These factors, particularly C/EBPalpha and C/EBPepsilon, have important roles in normal myelopoiesis. In addition, loss of C/EBP activity appears to have a role in the pathogenesis of myeloid disorders including acute myeloid leukemia (AML). Acute promyelocytic leukemia (APL) is a subtype of AML in which a role for C/EBPs has been postulated. In almost all cases of APL, a promyelocytic leukemia-retinoic acid receptor alpha (PML-RARalpha) fusion protein is expressed as a result of a t(15;17)(q22; q12) chromosomal translocation. PML-RARalpha. inhibits expression of C/EBPepsilon, whereas all-trans retinoic acid (tRA), a differentiating agent to which APL is particularly susceptible, induces C/EBPepsilon expression. PML-RARalpha may also inhibit C/EBPalpha activity. Thus, the effects of PML-RARalpha on C/EBPs may contribute to both the development of leukemia and the unique sensitivity of APL to tRA. We tested the hypothesis that increasing the activity of C/EBPs would revert the leukemic phenotype. C/EBPalpha and C/EBPe were introduced into the FDC-P1 myeloid cell line and into leukemic cells from PML-RARA transgenic mice. C/EBP factors suppressed growth and induced partial differentiation in vitro. In vivo, enhanced expression of C/EBPs prolonged survival. By using a tamoxifen-responsive version of C/EBPepsilon, we observed that C/EBPe could mimic the effect of tRA, driving neutrophilic differentiation in leukemic animals. Our results support the hypothesis that induction of C/EBP activity is a critical effect of tRA in APL. Furthermore, our findings suggest that targeted modulation of C/EBP activities could provide a new approach to therapy of AML. (C) 2003 by The American Society of Hematology.

DOI： 10.1182/blood-2002-05-1374

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC MICROBIOLOGY  

In a screen for proteins that interact with Jak2, we identified a previously uncharacterized 70-kDa protein and cloned the corresponding cDNA. The predicated sequence indicates that p70 contains an SH3 domain and a C-terminal domain with similarities to the catalytic motif of phosphoglycerate mutase. p70 transcripts were found in all tissues examined. Similarly, when an antibody raised against a C-terminal peptide to analyze p70 protein expression was used, all murine tissues examined were found to express p70. To investigate the in vivo role of p70, we generated a p70-deficient mouse strain. Mice lacking p70 are viable, develop normally, and do not display any obvious abnormalities. No differences were detected in various hematological parameters, including bone marrow colony-forming ability, in response to cytokines that utilize Jak2. In addition, no impairment in B- and T-cell development and proliferative ability was detected.

DOI： 10.1128/MCB.22.21.7491-7500.2002

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Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-LISS  

Recent studies have shown that point mutations in granulocyte colony-stimulating factor receptor (G-CSFR) are involved in the pathogenesis of severe congenital neutropenia (SCN) and in the transformation of SCN to acute myelogenous leukemia (AML). It is reasonably speculated that the abnormalities in the signal transduction pathways for G-CSF could be partly responsible for the pathogenesis and the development to AML in patients with myelodysplastic syndromes (MDS). Therefore, we investigated the structural and functional abnormalities of the G-CSFR in 14 patients with MDS and 10 normal subjects. In in vitro colony forming assay, MDS samples showed reduced response to growth factors. However, G-CSF, but not GM-CSF and IL-3, enhanced clonal growth in three cases of high risk patients with MDS (RAEB, RAEB-t, and MDS having progressed to acute myeloid leukemia (AML)) and one low risk patient (RA). Eight out of 14 patients including above 4 patients demonstrated a common deletion of the G-CSFR cDNA; a deletion of three nucleotides (2128-2130) in the juxtamembrane domain of the G-CSFR, which resulted in a conversion of Asn(630) Arg(631) to Lys(630). To assess the functional activities of this deletion in the G-CSFR isoform, a mutant with the same three-nucleotide deletion was constructed by site-directed mutagenesis. FDCP-2 cells expressing the G-CSFR isoform responded to G-CSF, and exhibited proliferative responses than did those cells having wild-type G-CSFR. Moreover, these isoforms showed prolonged activation of STAT3 in response to G-CSF than did the wild-type. These results suggest that the deletion in the juxtamembrane domain of the G-CSFR gives a growth advantage to abnormal MDS clones and may contribute to the pathogenesis of MDS. (C) 2002 Wiley-Liss, Inc.

DOI： 10.1002/jcp.10102

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN  

Platelet glycoprotein (GP) Ib/IX/V complex mediates high-shear dependent platelet activation through an interaction with the Von Willebrand factor (vWF), All four subunits of the complex have a structural motif, the leucine-rich repeat (LRR) sequence, with leucines in conserved positions. Here we report a new polymorphism. Leu/Phe at residue 70 of GPIbalpha, which disrupts the consensus sequence of the LRR in the vWF binding domain, Genotype frequencies among 142 healthy Japanese subjects were 92.3%, 7.7%, and 0.0%, for the (70)Leu/Leu, (70)Leu/Phe, and (70)Phe/Phe genotypes, respectively.
Ristocetin-induced or shear-induced platelet aggregation was not significantly different between the (70)Leu/Leu and (70)Leu/Phe genotypes. In in vitro studies, a recombinant GPIba fragment with (70)Phe (L70F) as compared to that With (70)Leu (WT) had low reactivity to anti-GPIbalpha monoclonal antibodies, GUR20-5 and Hip1, both of which recognize conformation-specific epitopes within the 45-kDa domain. Ristocetin-induced I-125-vWF binding to L70F, however, did not differ from that to WT.

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TACC3 is a centrosomal/mitotic spindle-associated protein that is highly expressed in a cell cycle-dependent manner in hematopoietic lineage cells. During embryonic development, TACC3 is expressed in a variety of tissues in addition to the hematopoietic lineages. TACC3 deficiency causes an embryonic lethality at mid- to late gestation involving several lineages of cells. Hematopoietic stem cells, while capable of terminal differentiation, are unable to be expanded in vitro or in vivo in reconstitution approaches. Although gross alterations in centrosome numbers and chromosomal segregation are not observed, TACC3 deficiency is associated with a high rate of apoptosis and expression of the p53 target gene, p21(Waf1/Cip1). Hematopoietic stem cell functions, as well as deficiencies in other cell lineages, can be rescued by combining the TACC3 deficiency with p53 deficiency. The results support the concept that TACC3 is a critical component of the centrosome/mitotic spindle apparatus and its absence triggers p53-mediated apoptosis.

DOI： 10.1093/emboj/21.4.653

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC HEMATOLOGY  

Granulocyte colony-stimulating factor (G-CSF) is a major cytokine that regulates proliferation and differentiation of myeloid cells, although the underlying mechanisms by which G-CSF controls myeloid differentiation are largely unknown. Differentiation of hematopoietic cells is regulated by lineage-specific transcription factors, and gene-targeting studies previously revealed the critical roles of CCAAT/enhancer-binding protein (C/EBP) alpha and C/EBP epsilon, respectively, in the early and mid-late stages of granulocyte differentiation, The expression of C/EBP epsilon in 32Dcl3 cells and FDCP1 cells expressing mutant G-CSF receptors was examined and it was found that G-CSF up-regulates C/EBP epsilon. The signal for this expression required the region containing the first tyrosine residue of G-CSF receptor. Dominant-negative signal transducers and activators of transcription 3 blocked G-CSF-induced granulocytic differentiation in 32D cells but did not block induction of C/EBP epsilon, indicating that these proteins work in different pathways. It was also found that overexpression of C/EBP epsilon greatly facilitated granulocytic differentiation by G-CSF and, surprisingly, that expression of C/EBP epsilon alone was sufficient to make cells differentiate into morphologically and functionally mature granulocytes. Overexpression of c-myc inhibits differentiation of hematopoietic cells, but the molecular mechanisms of this inhibition are not fully understood. In 32Dcl3 cells overexpressing c-myc that do not differentiate by means of G-CSF, induction of C/EBP epsilon is completely abrogated. Ectopic expression of C/EBP epsilon in these cells induced features of differentiation, including changes in nuclear morphologic characteristics and the appearance of granules. These data show that C/EBP epsilon constitutes a rate-limiting step in G-CSF-regulated granulocyte differentiation and that c-myc antagonizes G-CSF-induced myeloid differentiation, at least partly by suppressing induction of C/EBP epsilon. (C) 2001 by The American Society of Hematology.

DOI： 10.1182/blood.V98.4.897

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The erythropoietin receptor (EpoR) is required for the proliferation and survival of committed erythroid lineage cells. Previous studies have utilized receptor mutations to show the requirement for the distal half of the cytoplasmic domain of the EpoR and receptor tyrosines for activation of signaling pathways potentially critical to Epo function. To extend these studies to in vivo erythropoiesis, we have created two mutant strains of mice. One strain (H) contains a truncation of the distal half of the cytoplasmic domain, while the second strain (HM) contains the same truncation as well as the mutation of the residual tyrosine (Y-343) to a phenylalanine. Strikingly, both strains of mice are viable, with only slight alterations in constitutive erythropoiesis or in in vitro assays of red cell lineage function. Challenging H mutant mice with continuous injections of Epo results in an erythrocytosis that is not seen in HM mice. The results demonstrate that neither the distal region nor receptor tyrosines are essential for in vivo EpoR function, but contribute to receptor function in a subtle manner.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Retinoic acid (RA) and 1,25-dihydroxyvitamin D-3 (D-3) are well known for inducing differentiation in many leukemic cell lines. The nuclear signalling pathways of RA and D-3 are mediated through their cognate receptors, the retinoic acid receptor (RAR) and vitamin D-3 receptor (VDR), respectively. Retinoid X receptor (RXR) is an auxiliary factor that forms a heterodimer with RAR and VDR, enabling their efficient transcriptional activation. 9-cis RA, a high-affinity ligand for RXR, greatly enhanced D-3-induced CD14 expression in U937 cells, while RA alone did not induce CD14 expression. 9-cis RA also resulted in morphological changes of U937 cells to macrophage-like cells when combined with D-3, while RA alone resulted in granulocyte-like cells. RA and D-3 together enhanced c-fms expression, phagocytic activity, and acted synergistically to promote nitroblue tetrazolium reduction activity and inhibit proliferation. Northern analysis showed that U937 cells constitutively expressed RAR-alpha, VDR and RXR-alpha mRNAs. RA or D-3 alone or in combination did not affect RAR-alpha and VDR expression, while 9-cis RA and 9-cis RA plus all-trans RA significantly reduced RXR-alpha expression. Interestingly, D-3 could restore the down-regulation of RXR-alpha mRNA by 9-cis RA. These findings suggest that there is crossover of the nuclear signalling pathways of RA and D-3. This may have clinical implications in that RA and D-3 may be used in combination for differentiation-inducing therapy in acute myelogenous leukemia and myelodysplastic syndrome. Copyright (C) 1996 Elsevier Science Ltd.

DOI： 10.1016/0145-2126(96)00020-3

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DOI： 10.11406/rinketsu.37.208

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Other Link： http://search.jamas.or.jp/link/ui/1996205285

Language：English   Publishing type：Research paper (scientific journal)   Publisher：W B SAUNDERS CO  

Retinoic acid (RA) regulates the differentiation and proliferation of a wide variety of different cell types and all-trans RA induces complete remission in a high proportion of patients with acute promyelocytic leukemia (APL). However, clinical resistance to retinoids may develop and poses a serious problem for differentiation-inducing therapy. We studied the effects of RA in combination with a cytochrome P450 inhibitor (clotrimazole) and a P-glycoprotein antagonist (verapamil) on cell growth and differentiation of RA-resistant HL-60 cells and fresh HA-resistant leukemic cells from two APL patients. RA-resistant HL-60 cells and APL cells differentiated to mature granulocytes when cultured with all-trans RA and either clotrimazole and verapamil but not with either of the agents alone. These findings were confirmed in these cells by their increased expression of CD11b antigen and migration-inhibitory factor-related protein-8/14 mRNAs and decreased levels of c-myc mRNA. These combinations also markedly decreased the number of viable cells and inhibited cellular proliferation. After isolation of microsomes, measurements showed that levels of cytochrome P450 activities in both wild-type and RA-resistant HL-60 cells were almost comparable. Moreover, expression of the CYP1A1-type cytochrome P450 gene could not be detected in either cell type. However, RA-resistant HL-60 cells and APL cells, but not RA-sensitive HL-60 cells and APL cells, expressed multidrug-resistance-1 gene transcripts. Taken together, acquired resistance to RA may be explained in part by drug metabolism in leukemic cells. Possible mechanisms for accelerated clearance of RA include the induction of non-CYP1A1 cytochrome P450 enzymes and P-glycoprotein. (C) 1996 by The American Society of Hematology.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Keio University School of Medicine  

A 45-year-old woman with acute lymphoblastic leukemia (ALL) who failed to achieve complete remission (CR) after one course of induction chemotherapy with vincristine, daunorubicin, prednisolone and l-asparaginase was successfully treated with a high dose of cytosine arabinoside (Ara-C) and mitoxantrone. The leukemic blasts were CD7, 19, 33, and 38 antigens positive, and had a rearrangement in the T-cell receptor δ chain gene. The karyotype was normal. Primary induction failure and positivity for myeloid antigens are both reported to be poor prognostic factors for ALL. Nevertheless, this patient was successfully treated with the high dose Ara-C and mitoxantrone, and she remains in CR for over 20 months. Combination chemotherapy with high dose Ara-C and mitoxantron may be of benefit for refractory ALL with both CD7 and myeloid antigens.

DOI： 10.2302/kjm.45.114

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Language：Japanese   Publisher：The Japanese Society of Hematology  

A randomized treated/non-treated study of rG&middot;CSF (5 &mu;g/kg/d, d.i.v.) in patients with acute myelogenous leukemia was conducted to assess its efficacy on fever (&ge;38&deg;C) or documented infection after induction therapy. Of 95 patients enrolled, 46 patients were evaluable for safety and 43 for efficacy in the treated group of 47 patients while 37 of 48 patients were eligible for data analysis in the untreated group. Mare patients showed a recovery in the blood neutrophil count (to >1,000/&mu;<i>l</i>) during rG&middot;CSF treatment (14 days) than in the non-treated group (p=0.039) while the number of febrile patients and duration of fever did not significantly differ between the two groups. The treatment with rG&middot;CSF enabled an early recovery in neutrophil count in the patients with neutropenia and overt signs of infection after induction therapy, but there was no hastened allevistion of symptoms of infection in these patients.

DOI： 10.11406/rinketsu.36.597

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Other Link： http://search.jamas.or.jp/link/ui/1996038731

Language：English   Publisher：AMER ASSOC BLOOD BANKS  

Background: Transfusion-associated graft-versus-host disease (TA-GVHD) is a serious complication of blood transfusion that is characterized by high fever, a scaly maculopapular erythematous rash, diarrhea, hepatocellular damage with marked elevation of liver function test values, and pancytopenia. It can occur in immunocompetent as well as immunocompromised recipients, The existence of atypical TA-GVHD that resolves spontaneously and does not exhibit all of the manifestations has been suggested, but there has been to date no documented diagnosis of GVHD supported by evidence of engraftment.
Case Report: A female patient presented and was diagnosed with acute myelogenous leukemia (AML:M4), and, after unsuccessful combination chemotherapy, she received a transfusion and developed manifestation of TA-GVHD as well as evidence of chimerism. TA-GVHD was proved by demonstrating Y chromosome-specific genes in the skin by polymerase chain reaction. The manifestations of clinical GVHD abated within 4 months.
Conclusion: Polymerase chain reaction analysis of Y chromosomes in specimens from female patients is useful in the diagnosis of suspected cases of spontaneously resolving TA-GVHD.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：W B SAUNDERS CO  

Retinoic acids (RAs) exert pleiotropic effects on cellular growth and differentiation, All-trans retinoic acid (ATRA) and 9-cis retinoic acid (9-cis RA), a stereoisomer of ATRA, induce differentiation of leukemic cell lines and cells from patients with acute myelogenous leukemia (AML) in vitro, Despite information on the effects of RAs on hematopoietic cells, little is known about how RAs act on the hematopoietic microenvironment, especially on bone marrow stromal cells. Based on recent observations that various cytokines produced mainly by bone marrow stromal cells regulate hematopoiesis, we analyzed the effects of RAs on cytokine production by these cells. ATRA or g-cis RA treatment of human bone marrow stromal cell line KM101, which produces macrophage colony-stimulating factor (M-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) constitutively, enhanced mRNA levels of both cytokines in a dose-dependent manner, Both RAs also stimulated M-CSF production from primary cultures of human bone marrow stromal cells. Both retinoic acid receptor (RAR)-alpha and retinoid X receptor (RXR)-alpha were expressed constitutively in KM101 cells. ATRA did not affect the expression of either receptor, whereas 9-cis RA increased RXR-alpha mRNA expression in a dose-dependent manner, but did not affect levels of RAR-alpha mRNA. These findings may have important biologic implications for both the role of RAs in hematopoiesis and the therapeutic effects of ATRA on the hematopoietic microenvironment in patients with acute promyelocytic leukemia (APL). (C) 1994 by The American Society of Hematology.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-LISS  

Treatment of acute promyelocytic leukemia (APL) patients with all-trans retinoic acid (ATRA) was associated with rapid improvement in hemostatic markers. We made serial analyses of various hemostatic parameters in seven newly diagnosed APL patients. In all patients at diagnosis, plasma fibrinogen/fibrin degradation product (fragment-E), crosslinked fibrin degradation product (D-dimer fragment), thrombin-antithrombin III complex and plasmin-alpha(2)-plasmin inhibitor complex were elevated, indicating the presence of disseminated intravascular coagulation (DIC). Antithrombin III (ATIII) levels were normal in all patients except for the patient with congenital ATIII deficiency. In four patients subsequently treated with ATRA without anticoagulant therapy, these hemostatic markers returned to near-normal levels by day 7 of treatment, indicating that DIC was essentially resolved. By contrast, in three patients who received conventional chemotherapy with a continuous low-dose heparin, improvement of coagulopathy was slower than in patients treated with ATRA. These results suggest that ATRA therapy exerts the rapid improvement in abnormal hemostatic markers in APL patients without any anticoagulant therapies, by inducing differentiation of leukemic cells and, in turns no massive release of procoagulant or fibrinolytic substances from these cells. (C) 1994 Wiley-Liss, Inc.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：W B SAUNDERS CO  

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DOI： 10.11406/rinketsu.35.256

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC HEMATOLOGY  

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DOI： 10.1111/j.1365-2141.1991.tb04464.x

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We report a 69 year-old female with sarcoidosis who developed chronic thrombocytopenia, a rare complication of this disorder. Histologically normal bone marrow with increased number of megakaryocytes and high level of PAIgG strongly suggest the immune destruction of platelets as the cause of thrombocytopenia. In addition to thrombocytopenia, this case is also distinctive in its clinical manifestation. The patient developed several infrequent manifestations of sarcoidosis including complete AV block, uveitis, skin eruptions and middle lobe syndrome, but, did not have an intrathoracic adenopathy, the commonest manifestation of this disease. © 1990, The Keio Journal of Medicine. All rights reserved.

DOI： 10.2302/kjm.39.261

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：Japanese   Publisher：日本リウマチ学会-関東支部  

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Language：English   Publishing type：Book review, literature introduction, etc.   Publisher：Elsevier Inc.  

Posttranslational protein modification through addition of the O‐linked β-N-acetyl-D-glucosamine (O-GlcNAc) moiety to serine or threonine residues, termed O-GlcNAcylation, is a highly dynamic process conserved throughout eukaryotes. O-GlcNAcylation is reversibly catalyzed by a single pair of enzymes, O-GlcNAc transferase and O-GlcNAcase, and it acts as a fundamental regulator for a wide variety of biological processes including gene expression, cell cycle regulation, metabolism, stress response, cellular signaling, epigenetics, and proteostasis. O-GlcNAcylation is regulated by various intracellular or extracellular cues such as metabolic status, nutrient availability, and stress. Studies over decades have unveiled the profound biological significance of this unique protein modification in normal physiology and pathologic processes of diverse cell types or tissues. In hematopoiesis, recent studies have indicated the essential and pleiotropic roles of O-GlcNAcylation in differentiation, proliferation, and function of hematopoietic cells including T cells, B cells, myeloid progenitors, and hematopoietic stem and progenitor cells. Moreover, aberrant O-GlcNAcylation is implicated in the development of hematologic malignancies with dysregulated epigenetics, metabolism, and gene transcription. Thus, it is now recognized that O-GlcNAcylation is one of the key regulators of normal and malignant hematopoiesis.

DOI： 10.1016/j.exphem.2021.07.003

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER ASSOC IMMUNOLOGISTS  

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Language：English   Publishing type：Book review, literature introduction, etc.   Publisher：Elsevier Ltd  

Recent genomics studies have revealed that clonal hematopoietic expansion due to recurrent somatic mutations in hematopoietic cells are common in older people without evidence of hematological malignancies. This phenomenon, termed clonal hematopoiesis of indeterminate potential (CHIP), is associated with greater risk for hematological malignancy and cardiovascular diseases, leading to decreased overall survival of the affected individuals. The most frequently mutated genes in CHIP cases include genes associated with epigenetic modification, cell signaling, DNA damage response and RNA splicing, which are all recurrently mutated in myeloid malignancies. Recent findings suggest that these genetic alleles exert pleiotropic effects on hematopoietic stem cell (HSC) functions, transcriptional regulations, DNA damage responses and resistance to cellular stresses. Recent studies have uncovered the clinical relevance of CHIP in various settings during the management of hematological malignancies. Elucidating overall picture of clonal evolution based on CHIP will help developing preventive measures and novel treatments for hematological malignancies.

DOI： 10.1016/j.leukres.2020.106457

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Language：Japanese   Publisher：(一社)日本臨床免疫学会  

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54歳女性。抗リン脂質抗体症候群(APS)に対するエドキサバン内服中に腹痛、発熱、意識障害が出現した。前医ではAPSによる両側副腎出血性梗塞、副腎不全に伴う低ナトリウム血症として加療を受けたが、経過中に微小脳梗塞を認め、精査加療目的に当科転院となった。入院時検査では副腎梗塞、左前頭葉皮質下・後頭葉皮質の微小脳梗塞、APS腎症を認め、APSに対する抗凝固療法としてワルファリン投与を継続し、第63病日よりアスピリンを追加したところ、良好な経過が得られ、第96病日に退院となった。

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DOI： 10.1182/blood-2018-171

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Language：English   Publisher：(一社)日本血液学会-東京事務局  

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Language：Japanese   Publisher：関東リウマチ研究会  

症例1は34歳男性で、4年前より2〜3ヵ月ごとに数週間続く腹痛が出現し、前医消化器内科で精査を受けるも原因不明であった。今回、炎症高値の精査目的に当科紹介となった。当科受診以降も2ヵ月に1回程度の腹痛発作を認めていた。発作時は37.9℃程度の発熱を認めており、それに伴いCRPの上昇も認められた。その後、コルヒチン投与を開始したところ、症状は速やかに消失し、CRP陰性化を認めた。症例2は41歳男性で、3年前より1ヵ月に2回程度、38℃台の発熱や腹痛を自覚していた。その後、当院外科紹介となり、遺残胆石摘出術が施行された。術後、抗菌薬加療をされていたが、40℃台の発熱、CRP高値が遷延したため当科併診となった。コルヒチンを開始したところ、初めて解熱や症状消失、CRPの陰性化を認め、以降、発熱、腹痛ともに認めていない。

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Language：Japanese   Publisher：日本リウマチ学会-関東支部  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER SCIENCE BV  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：WILEY  

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Language：Japanese   Publisher：(一社)日本アレルギー学会  

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Language：English   Publisher：(一社)日本リウマチ学会  

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Language：English   Publisher：(一社)日本リウマチ学会  

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：English   Publisher：(一社)日本リウマチ学会  

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：English   Publisher：(一社)日本リウマチ学会  

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Language：English   Publisher：(一社)日本リウマチ学会  

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Language：Japanese   Publisher：関東リウマチ研究会  

症例は28歳時に関節リウマチの既往があった。5年前よりレイノー症状、頬部紅斑が出現し、今回、労作時呼吸困難と両側下腿浮腫を認めた。心エコーで肺高血圧症が疑われ精査目的に当科入院となった。顔面紅斑、蛋白尿、LAC陽性、心膜炎を疑う所見から、抗ds-DNA抗体、抗核抗体、抗Sm抗体陰性と非典型的であったがSLEと考え、心筋炎、PHの合併例として先行して治療を開始した。入院直後からPSLを増量し、心筋炎、血管炎の合併を考慮し、第10病日にIVCY、続けてステロイドパルスを施行した。また、初診時にNYHA IIIの両心不全を合併しており、血圧コントロールと心不全治療のため、利尿薬に加えACE阻害薬を開始した。心不全治療と免疫抑制治療で自覚症状、データ、エコー所見は改善した。IVCY 2回目施行後、蛋白尿はほぼ陰性化し、NYHAも改善が得られた。

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER SOC HEMATOLOGY  

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DOI： 10.1158/1538-7445.AM2014-3439

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CiNii Books

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Language：Japanese   Publisher：(NPO)日本小児がん学会  

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Other Link： http://search.jamas.or.jp/link/ui/2007149353

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DOI： 10.1182/blood.V108.11.1938.1938

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DOI： 10.1093/emboj/20.23.6836

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