Stage-Specific Human Induced Pluripotent Stem Cells Map the Progression of Myeloid Transformation to Transplantable Leukemia
Stage-Specific Human Induced Pluripotent Stem Cells Map the Progression of Myeloid Transformation to Transplantable Leukemia
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DOI：
10.1016/j.stem.2017.01.009
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发表时间：
2017-03-02
期刊：
影响因子：
23.9
通讯作者：
Papapetrou, Eirini P.
中科院分区：
文献类型：
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作者：
Kotini, Andriana G.;Chang, Chan-Jung;Papapetrou, Eirini P.
骨髓恶性肿瘤越来越多地被视为一种疾病谱，包括从克隆造血到骨髓增生异常综合征（MDS）和急性髓性白血病（AML）的表型连续体中延伸的造血疾病。在这项研究中，我们获得了一系列诱导多能干细胞（iPSC）系，这些细胞系捕获了一系列疾病阶段，包括白血病前期、低风险MDS、高风险MDS和继发性AML。在他们的分化，我们发现造血表型的分级严重性和/或阶段特异性，共同描绘了一个表型路线图的疾病进展，最终在连续移植白血病。我们还表明，疾病阶段的转变，包括逆转和进展，可以在这个系统中使用基因校正或通过CRISPR/Cas9引入突变来建模，并且这种基于iPSC的方法可以用于揭示疾病阶段对药物的特异性反应。因此，我们的研究提供了深入了解界定髓系转化的启动和进展的细胞事件，以及测试遗传和药物干预的新平台。
Myeloid malignancy is increasingly viewed as a disease spectrum, comprising hematopoietic disorders that extend across a phenotypic continuum ranging from clonal hematopoiesis to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). In this study, we derived a collection of induced pluripotent stem cell (iPSC) lines capturing a range of disease stages encompassing preleukemia, low-risk MDS, high-risk MDS, and secondary AML. Upon their differentiation, we found hematopoietic phenotypes of graded severity and/or stage specificity that together delineate a phenotypic roadmap of disease progression culminating in serially transplantable leukemia. We also show that disease stage transitions, both reversal and progression, can be modeled in this system using genetic correction or introduction of mutations via CRISPR/Cas9 and that this iPSC-based approach can be used to uncover disease-stage-specific responses to drugs. Our study therefore provides insight into the cellular events demarcating the initiation and progression of myeloid transformation and a new platform for testing genetic and pharmacological interventions.