title: 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 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.
authors.affiliation: Oncogenesis and Development Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD
authors.forename: Jon P
authors.initials: JP
authors.lastname: Connelly
authors.forename: Erika M
authors.initials: EM
authors.lastname: Kwon
authors.forename: Yongxing
authors.initials: Y
authors.lastname: Gao
authors.forename: Niraj S
authors.initials: NS
authors.lastname: Trivedi
authors.forename: Abdel G
authors.initials: AG
authors.lastname: Elkahloun
authors.forename: Marshall S
authors.initials: MS
authors.lastname: Horwitz
authors.forename: Linzhao
authors.initials: L
authors.lastname: Cheng
authors.forename: P Paul
authors.initials: PP
authors.lastname: Liu
mesh_terms: D000818:Animals; D025861:Blood Coagulation Disorders, Inherited / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D001791:Blood Platelet Disorders / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D050676:Core Binding Factor Alpha 2 Subunit / Q000737:chemistry / Q000235:genetics*; D020869:Gene Expression Profiling; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D051379:Mice; D020125:Mutation, Missense; D052416:Targeted Gene Repair / Q000379:methods*; D034061:Thrombopoiesis / Q000235:genetics
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; C493728:RUNX1 protein, human
references.citation: Exp Hematol. 2010 May;38(5):403-16
references.pmid: 20206228
references.citation: J Natl Cancer Inst. 1976 Feb;56(2):245-63
references.pmid: 1255758
references.citation: Blood. 2010 Apr 8;115(14):2806-9
references.pmid: 20154212
references.citation: Cell Stem Cell. 2009 Jul 2;5(1):97-110
references.pmid: 19540188
references.citation: Blood. 2005 Sep 1;106(5):1601-3
references.pmid: 15914555
references.citation: Blood. 2005 Jun 15;105(12):4664-70
references.pmid: 15741216
references.citation: Blood. 2012 Sep 27;120(13):2708-18
references.pmid: 22898599
references.citation: Blood. 2004 Dec 1;104(12):3565-72
references.pmid: 15297309
references.citation: Annu Rev Med. 2013;64:277-90
references.pmid: 23327523
references.citation: Nature. 2009 Feb 12;457(7231):892-5
references.pmid: 19182774
references.citation: Blood. 1985 Mar;65(3):557-63
references.pmid: 3855665
references.citation: Nat Methods. 2011 May;8(5):409-12
references.pmid: 21460823
references.citation: Nat Med. 2004 Mar;10(3):299-304
references.pmid: 14966519
references.citation: Cell. 1996 Jan 26;84(2):321-30
references.pmid: 8565077
references.citation: Proc Natl Acad Sci U S A. 1996 Apr 16;93(8):3444-9
references.pmid: 8622955
references.citation: Nat Genet. 1999 Oct;23(2):166-75
references.pmid: 10508512
references.citation: Br J Haematol. 2006 Sep;134(5):453-66
references.pmid: 16856888
references.citation: Leuk Lymphoma. 2004 Jan;45(1):1-10
references.pmid: 15061191
references.citation: Blood. 2002 Feb 15;99(4):1364-72
references.pmid: 11830488
references.citation: N Engl J Med. 1969 Dec 4;281(23):1264-70
references.pmid: 5349805
references.citation: Cell Stem Cell. 2012 Jun 14;10(6):678-684
references.pmid: 22704507
references.citation: Leuk Lymphoma. 2010 Oct;51(10):1931-5
references.pmid: 20846103
references.citation: Blood. 1999 Mar 15;93(6):1817-24
references.pmid: 10068652
references.citation: Ann Hematol. 2008 Feb;87(2):131-7
references.pmid: 17952438
references.citation: Blood. 2004 Feb 1;103(3):948-54
references.pmid: 14525764