PUBLICATION

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

Authors
Connelly, J.P., Kwon, E.M., Gao, Y., Trivedi, N.S., Elkahloun, A.G., Horwitz, M.S., Cheng, L., Liu, P.P.
ID
ZDB-PUB-140813-3
Date
2014
Source
Blood   124(12): 1926-30 (Journal)
Registered Authors
Liu, Pu Paul
Keywords
none
MeSH Terms
  • Animals
  • Blood Coagulation Disorders, Inherited/genetics*
  • Blood Coagulation Disorders, Inherited/pathology
  • Blood Coagulation Disorders, Inherited/therapy*
  • Blood Platelet Disorders/genetics*
  • Blood Platelet Disorders/pathology
  • Blood Platelet Disorders/therapy*
  • Core Binding Factor Alpha 2 Subunit/chemistry
  • Core Binding Factor Alpha 2 Subunit/genetics*
  • Gene Expression Profiling
  • Humans
  • Induced Pluripotent Stem Cells/metabolism
  • Induced Pluripotent Stem Cells/pathology
  • Induced Pluripotent Stem Cells/transplantation
  • Leukemia, Myeloid, Acute/genetics*
  • Leukemia, Myeloid, Acute/pathology
  • Leukemia, Myeloid, Acute/therapy*
  • Mice
  • Mutation, Missense*
  • Targeted Gene Repair/methods*
  • Thrombopoiesis/genetics
PubMed
25114263 Full text @ Blood
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.
Genes / Markers
Figures
Show all Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes