Studying clonal evolution of myeloid malignancies using induced pluripotent stem cells.
Studying clonal evolution of myeloid malignancies using induced pluripotent stem cells.
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DOI：
10.1097/moh.0000000000000620
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发表时间：
2021-01
影响因子：
3.2
通讯作者：
Papapetrou EP
中科院分区：
文献类型：
--
作者：
Doulatov S;Papapetrou EP
髓系恶性肿瘤包括一系列遗传异质性疾病，其特征是逐步获得体细胞突变和克隆进化。患者的血液和骨髓通常由沿着克隆进化路径的不同克隆和亚克隆的混合物组成，这不能用大多数当前的方法进行反卷积。在此，我们综述了诱导多能干细胞（iPSC）技术在这些疾病的克隆构建和克隆进化研究中的应用，重点是骨髓增生异常综合征和急性髓系白血病。重编程为多能性允许捕获单个体细胞的基因组，使其成为稳定的iPSC系。此外，精确的基因组编辑可以将特定的驱动突变（分离的或组合的）引入正常的iPSCs。利用这些方法的研究已经阐明了髓系肿瘤患者的克隆组成和突变顺序。重要的是，它们还能够对单个突变及其组合的细胞和分子后果进行功能性调查，并允许测试药物对不同疾病克隆的影响。人类多能干细胞是阐明从正常造血到恶性造血进展机制的重要工具，并为药物测试和药物发现提供了支持。
Myeloid malignancies comprise a spectrum of genetically heterogeneous disorders marked by the stepwise acquisition of somatic mutations and clonal evolution. The blood and bone marrow of patients typically consists of a mix of different clones and subclones along the path of clonal evolution that cannot be deconvoluted with most current approaches. Here, we review the application of induced pluripotent stem cell (iPSC) technology to the study of the clonal architecture and clonal evolution of these diseases, focusing on myelodysplastic syndromes and acute myeloid leukemia. Reprogramming to pluripotency allows capture of the genomes of single somatic cells into stable iPSC lines. In addition, precise genome editing can introduce specific driver mutations, isolated, and in combinations, into normal iPSCs. Studies utilizing these approaches have elucidated the clonal composition and mutational order in patients with myeloid neoplasms. Importantly, they have also enabled functional interrogation of the cellular and molecular consequences of individual mutations and their combinations and allowed testing of the effects of drugs on distinct disease clones. Human iPSCs are important tools to elucidate the mechanisms of progression from normal to malignant haematopoiesis and empower drug testing and drug discovery.