University of Massachusetts Medical School Faculty Publications

Title

A germline point mutation in Runx1 uncouples its role in definitive hematopoiesis from differentiation

UMMS Affiliation

Department of Cell and Developmental Biology; Department of Microbiology and Physiological Systems

Date

11-2013

Document Type

Article

Medical Subject Headings

Animals; B-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

Disciplines

Cell Biology | Cellular and Molecular Physiology | Developmental Biology

Abstract

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.

Rights and Permissions

Citation: 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 site

Related Resources

Link to Article in PubMed

PubMed ID

23823022