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Targeted gene correction of RUNX1 in induced pluripotent stem cells derived from familial platelet disorder with propensity to myeloid malignancy restores normal megakaryopoiesis.
- Source :
-
Experimental hematology [Exp Hematol] 2015 Oct; Vol. 43 (10), pp. 849-57. Date of Electronic Publication: 2015 Jun 11. - Publication Year :
- 2015
-
Abstract
- Familial platelet disorder with propensity to acute myeloid leukemia (FPD/AML) is an autosomal dominant disease associated with a germline mutation in the RUNX1 gene and is characterized by thrombocytopenia and an increased risk of developing myeloid malignancies. We generated induced pluripotent stem cells (iPSCs) from dermal fibroblasts of a patient with FPD/AML possessing a nonsense mutation R174X in the RUNX1 gene. Consistent with the clinical characteristics of the disease, FPD iPSC-derived hematopoietic progenitor cells were significantly impaired in undergoing megakaryocytic differentiation and subsequent maturation, as determined by colony-forming cell assay and surface marker analysis. Notably, when we corrected the RUNX1 mutation using transcription activator-like effector nucleases in conjunction with a donor plasmid containing normal RUNX1 cDNA sequences, megakaryopoiesis and subsequent maturation were restored in FPD iPSC-derived hematopoietic cells. These findings clearly indicate that the RUNX1 mutation is robustly associated with thrombocytopenia in patients with FPD/AML, and transcription activator-like effector nuclease-mediated gene correction in iPSCs generated from patient-derived cells could provide a promising clinical application for treatment of the disease.<br /> (Copyright © 2015 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Adult
DNA, Complementary genetics
Female
Humans
Induced Pluripotent Stem Cells pathology
Blood Coagulation Disorders, Inherited genetics
Blood Coagulation Disorders, Inherited metabolism
Blood Coagulation Disorders, Inherited pathology
Blood Coagulation Disorders, Inherited therapy
Blood Platelet Disorders genetics
Blood Platelet Disorders metabolism
Blood Platelet Disorders pathology
Blood Platelet Disorders therapy
Codon, Nonsense
Core Binding Factor Alpha 2 Subunit biosynthesis
Core Binding Factor Alpha 2 Subunit genetics
Genetic Therapy methods
Induced Pluripotent Stem Cells metabolism
Leukemia, Myeloid, Acute genetics
Leukemia, Myeloid, Acute metabolism
Leukemia, Myeloid, Acute pathology
Leukemia, Myeloid, Acute therapy
Thrombopoiesis genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1873-2399
- Volume :
- 43
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Experimental hematology
- Publication Type :
- Academic Journal
- Accession number :
- 26021490
- Full Text :
- https://doi.org/10.1016/j.exphem.2015.05.004