Targeted Correction of RUNX1 Mutation in FPD Patient-specific Induced Pluripotent Stem Cells Rescues Megakaryopoietic Defects

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2014 Aug 13

PMID 25114263

Citations 41

Authors

Jon P Connelly

Erika M Kwon

Yongxing Gao

Niraj S Trivedi

Abdel G Elkahloun

Marshall S Horwitz

Linzhao Cheng

P Paul Liu

Affiliations

Soon will be listed here.

Abstract

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 Runx11/2 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.

Citing Articles

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