Targeted correction of RUNX1 mutation in FPD patient-specific induced pluripotent stem cells rescues megakaryopoietic defects

ABSTRACT: Familial platelet disorder with predisposition to acute myeloid leukemia (FPD/AML) is an autosomal dominant disease of the hematopoietic system, which 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. Currently no suitable animal models exist for FPD/AML as Runx1+/- mice and zebrafish do not develop bleeding disorders or leukemia. Here we derived induced pluripotent stem cells (iPSCs) from two 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 one 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. Here, we derived iPSCs from two FPD/AML patients and demonstrated that these iPSCs have a megakaryopoietic defect in culture. Importantly we were able to rescue the megakaryopoietic defect by correcting the RUNX1 mutation with a gene targeting strategy enhanced by zinc finger nucleases (ZFNs). Three independent samples were obtained for each time point.

ORGANISM(S): Homo sapiens

SUBMITTER: abdel elkahloun 

PROVIDER: E-GEOD-54295 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress