担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

DOI： 10.1007/s12185-025-03929-x

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その他リンク： https://link.springer.com/article/10.1007/s12185-025-03929-x/fulltext.html

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

Abstract

Background

The molecular pathogenesis of acute myeloid leukemia (AML) was dramatically clarified over the latest two decades. Several important molecular markers were discovered in patients with AML that have helped to improve the risk stratification. However, developing new treatment strategies for relapsed/refractory acute myeloid leukemia (AML) is crucial due to its poor prognosis.

Procedure

To overcome this difficulty, we performed an assay for transposase‐accessible chromatin with sequencing (ATAC‐seq) in 10 AML patients with various gene alterations. ATAC‐seq is based on direct in vitro sequencing adaptor transposition into native chromatin, and is a rapid and sensitive method for integrative epigenomic analysis. ATAC‐seq analysis revealed increased accessibility of the DOCK1 gene in patients with AML harboring poor prognostic factors. Following the ATAC‐seq results, quantitative reverse transcription polymerase chain reaction was used to measure DOCK1 gene expression levels in 369 pediatric patients with de novo AML.

Results

High DOCK1 expression was detected in 132 (37%) patients. The overall survival (OS) and event‐free survival (EFS) among patients with high DOCK1 expression were significantly worse than those patients with low DOCK1 expression (3‐year EFS: 34% vs. 60%, p < .001 and 3‐year OS: 60% vs. 80%, p < .001). To investigate the significance of high DOCK1 gene expression, we transduced DOCK1 into MOLM14 cells, and revealed that cytarabine in combination with DOCK1 inhibitor reduced the viability of these leukemic cells.

Conclusions

Our results indicate that a DOCK1 inhibitor might reinforce the effects of cytarabine and other anti‐cancer agents in patients with AML with high DOCK1 expression.

DOI： 10.1002/pbc.31151

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Abstract

Mutations in the MECOM encoding EVI1 are observed in infants who have radioulnar synostosis with amegakaryocytic thrombocytopenia. MECOM-associated syndrome was proposed based on clinical heterogeneity. Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for progressive bone marrow failure. However, data regarding allogeneic HSCT for this rare disease are limited. We retrospectively assessed overall survival, conditioning regimen, regimen-related toxicities and long-term sequelae in six patients treated with allogeneic HSCT. All patients received a reduced-intensity conditioning (RIC) regimen consisting of fludarabine, cyclophosphamide or melphalan, and rabbit anti-thymocyte globulin and/or low-dose total body/thoracic-abdominal/total lymphoid irradiation, followed by allogeneic bone marrow or cord blood transplantation from unrelated donors between 4 and 18 months of age. All patients survived and achieved stable engraftment and complete chimerization with the donor type. Moreover, no patient experienced severe regimen-related toxicities, and only lower grades of acute graft-versus-host disease were observed. Three patients treated with low-dose irradiation had relatively short stature compared to three patients not treated with irradiation. Therefore, allogeneic HSCT with RIC is an effective and feasible treatment for infants with MECOM-associated syndrome. Future studies are needed to evaluate the use of low-dose irradiation to avoid risks of other long-term sequelae.

DOI： 10.1007/s12185-022-03505-7

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その他リンク： https://link.springer.com/article/10.1007/s12185-022-03505-7/fulltext.html

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：American Society of Hematology  

Abstract

We investigated genome-wide DNA methylation patterns in 64 pediatric patients with acute myeloid leukemia (AML). Based on unsupervised clustering with the 567 most variably methylated cytosine guanine dinucleotide (CpG) sites, patients were categorized into 4 clusters associated with genetic alterations. Clusters 1 and 3 were characterized by the presence of known favorable prognostic factors, such as RUNX1-RUNX1T1 fusion and KMT2A rearrangement with low MECOM expression, and biallelic CEBPA mutations (all 8 patients), respectively. Clusters 2 and 4 comprised patients exhibiting molecular features associated with adverse outcomes, namely internal tandem duplication of FLT3 (FLT3-ITD), partial tandem duplication of KMT2A, and high PRDM16 expression. Depending on the methylation values of the 1243 CpG sites that were significantly different between FLT3-ITD+ and FLT3-ITD− AML, patients were categorized into 3 clusters: A, B, and C. The STAT5-binding motif was most frequently found close to the 1243 CpG sites. All 8 patients with FLT3-ITD in cluster A harbored high PRDM16 expression and experienced adverse events, whereas only 1 of 7 patients with FLT3-ITD in the other clusters experienced adverse events. PRDM16 expression levels were also related to DNA methylation patterns, which were drastically changed at the cutoff value of PRDM16/ABL1 = 0.10. The assay for transposase-accessible chromatin sequencing of AMLs supported enhanced chromatin accessibility around genomic regions, such as HOXB cluster genes, SCHIP1, and PRDM16, which were associated with DNA methylation changes in AMLs with FLT3-ITD and high PRDM16 expression. Our results suggest that DNA methylation levels at specific CpG sites are useful to support genetic alterations and gene expression patterns of patients with pediatric AML.

DOI： 10.1182/bloodadvances.2021005381

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

Summary

KIT D816V mutation within exon 17 has been particularly reported as one of the poor prognostic factors in pediatric acute myeloid leukemia (AML) with RUNX1‐RUNX1T1. The exact frequency and the prognostic impact of KIT D816V minor clones at diagnosis were not examined. In this study, the minor clones were examined and the prognostic significance of KIT D816V mutation in pediatric patients was investigated. Consequently, 24 KIT D816V mutations (7.2%) in 335 pediatric patients were identified, and 12 of 24 were only detected via the digital droplet polymerase chain reaction method. All 12 patients were confined in core binding factor (CBF)‐AML patients. The 5 year event‐free survival of the patients with KIT D816V mutation was significantly inferior to those without KIT D816V mutation (44.1% [95% confidence interval (CI), 16.0%–69.4%] vs. 74.7% [95% CI, 63.0%–83.2%] P‐value = 0.02, respectively). The 5 year overall survival was not different between the two groups (92.9% [95% CI, 59.0%–NA vs. 89.7% [95% CI, 69.6%–96.8%] P‐value = 0.607, respectively). In this study, KIT D816V minor clones in patients with CBF‐AML were confirmed and KIT D816V was considered as a risk factor for relapse in patients with RUNX1‐RUNX1T1‐positive AML.

DOI： 10.1111/bjh.17569

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その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/bjh.17569

記述言語：日本語   出版者・発行元：科学評論社  

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記述言語：日本語   出版者・発行元：科学評論社  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：WILEY  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER SOC HEMATOLOGY  

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DOI： 10.1182/blood-2019-127656

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