Brief Report: Human Acute Myeloid Leukemia Reprogramming to Pluripotency Is a Rare Event and Selects for Patient Hematopoietic Cells Devoid of Leukemic Mutations
Brief Report: Human Acute Myeloid Leukemia Reprogramming to Pluripotency Is a Rare Event and Selects for Patient Hematopoietic Cells Devoid of Leukemic Mutations
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DOI：
10.1002/stem.2655
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发表时间：
2017-09-01
期刊：
影响因子：
5.2
通讯作者：
Bhatia, Mickie
中科院分区：
文献类型：
--
作者：
Lee, Jong-Hee;Salci, Kyle R.;Bhatia, Mickie
诱导多能干细胞重编程通过对遗传学和相关临床病理生理学进行建模，为疾病过程提供了重要见解。人类癌症代表了高度多样的遗传学，以及患者间和患者内的异质性，其中能够捕获这种疾病复杂性的细胞模型系统将是非常宝贵的。急性髓性白血病（AML）是最异质性的癌症之一，几十年来已被分为与独特风险分层相关的遗传亚型。在这里，我们报告了我们的努力，以诱导多能性的异质人群的人类患者，代表这种疾病在临床上。使用强大的优化重编程方法，我们证明了携带白血病基因组畸变的AML细胞的重编程是一种罕见的事件，除了那些具有从头混合谱系白血病（MLL）突变的细胞可以在体外重编程和模型药物反应。我们的研究结果表明，与缺乏基因组畸变的造血细胞不同，携带驱动突变的AML细胞对重编程是难治的。AML细胞中MLL融合蛋白的表达不有助于诱导的重编程成功，其继续选择缺乏AML患者特异性畸变的患者来源的细胞。我们的研究表明，实现多能性的意外阻断存在于大多数转化的AML患者细胞中。
Induced pluripotent stem cell reprogramming has provided critical insights into disease processes by modeling the genetics and related clinical pathophysiology. Human cancer represents highly diverse genetics, as well as inter- and intra-patient heterogeneity, where cellular model systems capable of capturing this disease complexity would be invaluable. Acute myeloid leukemia (AML) represents one of most heterogeneous cancers and has been divided into genetic subtypes correlated with unique risk stratification over the decades. Here, we report our efforts to induce pluripotency from the heterogeneous population of human patients that represents this disease in the clinic. Using robust optimized reprogramming methods, we demonstrate that reprogramming of AML cells harboring leukemic genomic aberrations is a rare event with the exception of those with de novo mixed-lineage leukemia (MLL) mutations that can be reprogrammed and model drug responses in vitro. Our findings indicate that unlike hematopoietic cells devoid of genomic aberrations, AML cells harboring driver mutations are refractory to reprogramming. Expression of MLL fusion proteins in AML cells did not contribute to induced reprogramming success, which continued to select for patient derived cells devoid of AML patient-specific aberrations. Our study reveals that unanticipated blockades to achieving pluripotency reside within the majority of transformed AML patient cells.