Dissecting stepwise mutational impairment of megakaryopoiesis in a model of Down syndrome-associated leukemia.
Dissecting stepwise mutational impairment of megakaryopoiesis in a model of Down syndrome-associated leukemia.
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DOI：
10.1172/jci161659
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发表时间：
2022-07-15
影响因子：
15.9
通讯作者：
DeGregori, James
中科院分区：
文献类型：
--
作者：
Evans, Edward J., Jr.;DeGregori, James
唐氏综合征（DS）患者患急性巨核母细胞白血病（AMKL）的风险增加了100倍以上，但其发病机制尚不清楚。在这一期的JCI中，Arkoun等人在来自DS患者的人类诱导多能干细胞（iPSC）克隆中逐步设计了DS- amkl相关的GATA1、MPL和SMC3突变，以分析每种突变如何影响基因表达控制和巨核细胞分化。作者表明，这些突变共同促进了短暂性骨髓增生性疾病向DS-AMKL的进展。这项研究强调了突变顺序和环境在血液恶性肿瘤进化过程中转录和分化途径的干扰的重要性，这将对预防和治疗干预的发展至关重要。
Individuals with Down syndrome (DS) have more than 100-fold increased risk of acute megakaryoblastic leukemia (AMKL), but its pathogenesis is poorly understood. In this issue of the JCI, Arkoun et al. engineered stepwise DS-AMKL–associated mutations in GATA1, MPL, and SMC3 in human induced pluripotent stem cell (iPSC) clones from individuals with DS to dissect how each mutation affects gene expression control and megakaryocytic differentiation. The authors showed that the mutations cooperatively promote progression from transient myeloproliferative disorder to DS-AMKL. This study highlights the importance of mutation order and context in the perturbations of transcriptional and differentiation pathways involved in the evolution of hematologic malignancies, which will be critical for the development of preventative and therapeutic interventions.