A germline point mutation in Runx1 uncouples its role in definitive hematopoiesis from differentiation
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Authors
Dowdy, Christopher R.Frederick, Dana
Zaidi, Sayyed K.
Colby, Jennifer L.
Lian, Jane B.
van Wijnen, Andre J.
Gerstein, Rachel M.
Stein, Janet L.
Stein, Gary S.
UMass Chan Affiliations
Department of Microbiology and Physiological SystemsDepartment of Cell and Developmental Biology
Document Type
Journal ArticlePublication Date
2013-11-01Keywords
AnimalsB-Lymphocytes
Cell Differentiation
Cell Proliferation
Cells, Cultured
Core Binding Factor Alpha 2 Subunit
Embryo, Mammalian
Flow Cytometry
Gene Expression Regulation, Developmental
*Germ-Line Mutation
Hematopoiesis
Hematopoietic Stem Cells
Lymphopoiesis
Mice
Mice, Inbred C57BL
Mice, Transgenic
Microscopy, Fluorescence
*Point Mutation
Reverse Transcriptase Polymerase Chain Reaction
T-Lymphocytes
Cell Biology
Cellular and Molecular Physiology
Developmental Biology
Metadata
Show full item recordAbstract
Definitive hematopoiesis requires the master hematopoietic transcription factor Runx1, which is a frequent target of leukemia-related chromosomal translocations. Several of the translocation-generated fusion proteins retain the DNA binding activity of Runx1, but lose subnuclear targeting and associated transactivation potential. Complete loss of these functions in vivo resembles Runx1 ablation, which causes embryonic lethality. We developed a knock-in mouse that expresses full-length Runx1 with a mutation in the subnuclear targeting cofactor interaction domain, Runx1(HTY350-352AAA). Mutant mice survive to adulthood, and hematopoietic stem cell emergence appears to be unaltered. However, defects are observed in multiple differentiated hematopoietic lineages at stages where Runx1 is known to play key roles. Thus, a germline mutation in Runx1 reveals uncoupling of its functions during developmental hematopoiesis from subsequent differentiation across multiple hematopoietic lineages in the adult. These findings indicate that subnuclear targeting and cofactor interactions with Runx1 are important in many compartments throughout hematopoietic differentiation. Elsevier Inc. All rights reserved.Source
Dowdy CR, Frederick D, Zaidi SK, Colby JL, Lian JB, van Wijnen AJ, Gerstein RM, Stein JL, Stein GS. A germline point mutation in Runx1 uncouples its role in definitive hematopoiesis from differentiation. Exp Hematol. 2013 Nov;41(11):980-991.e1. doi: 10.1016/j.exphem.2013.06.006. Link to article on publisher's siteDOI
10.1016/j.exphem.2013.06.006Permanent Link to this Item
http://hdl.handle.net/20.500.14038/30134PubMed ID
23823022Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1016/j.exphem.2013.06.006