Targeted correction of RUNX1 mutation in FPD patient-specific induced pluripotent stem cells rescues megakaryopoietic defects
Targeted correction of RUNX1 mutation in FPD patient-specific induced pluripotent stem cells rescues megakaryopoietic defects
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DOI：
10.1182/blood-2014-01-550525
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发表时间：
2014-09-18
期刊：
影响因子：
20.3
通讯作者：
Liu, P. Paul
中科院分区：
文献类型：
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作者：
Connelly, Jon P.;Kwon, Erika M.;Liu, P. Paul
易患急性髓系白血病（FPD/AML）的家族性血小板疾病是一种造血系统常染色体显性遗传疾病，由 RUNX1 杂合突变引起。 FPD/AML 患者患有以血小板减少症为特征的出血性疾病，血小板数量和功能降低，并且有发展为 AML 的倾向。不存在适合 FPD/AML 的动物模型，因为 Runx1(+/-) 小鼠和斑马鱼不会出现出血性疾病或白血病。在这里，我们从一个 FPD/AML 家族的 2 名患者身上提取了诱导多能干细胞 (iPSC)，发现 FPD iPSC 在体外表现出巨核细胞分化缺陷。我们通过基因打靶纠正了 1 个 FPD iPSC 系中的 RUNX1 突变，从而使培养物中 iPSC 的巨核细胞生成正常化。我们的结果证明使用患者特异性 iPSC 成功进行 FPD 体外建模，并证实 RUNX1 突变是 FPD 患者巨核细胞生成缺陷的原因。
Familial platelet disorder with predisposition to acute myeloid leukemia (FPD/AML) is an autosomal dominant disease of the hematopoietic system that is caused by heterozygous mutations in RUNX1. FPD/AML patients have a bleeding disorder characterized by thrombocytopenia with reduced platelet numbers and functions, and a tendency to develop AML. No suitable animal models exist for FPD/AML, as Runx1(+/-) mice and zebra fish do not develop bleeding disorders or leukemia. Here we derived induced pluripotent stem cells (iPSCs) from 2 patients in a family with FPD/AML, and found that the FPD iPSCs display defects in megakaryocytic differentiation in vitro. We corrected the RUNX1 mutation in 1 FPD iPSC line through gene targeting, which led to normalization of megakaryopoiesis of the iPSCs in culture. Our results demonstrate successful in vitro modeling of FPD with patient-specific iPSCs and confirm that RUNX1 mutations are responsible for megakaryopoietic defects in FPD patients.