Open AccessDual requirement for the ETS transcription factors Fli-1 and Erg in hematopoietic stem cells and the megakaryocyte lineage
Author(s) -
Elizabeth Kruse,
Stephen J. Loughran,
Tracey M. Baldwin,
Emma C. Josefsson,
Sarah Ellis,
Dennis K. Watson,
Paquita Nurden,
Donald Metcalf,
Douglas J. Hilton,
Warren S. Alexander,
Benjamin T. Kile
Publication year - 2009
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0906556106
Subject(s) - biology , megakaryocyte , haematopoiesis , ets transcription factor family , stem cell , erg , progenitor cell , transcription factor , cancer research , heterozygote advantage , hematopoietic stem cell , genetics , microbiology and biotechnology , immunology , gene , allele , retina , neuroscience
Fli-1 and Erg are closely related members of the Ets family of transcription factors. Both genes are translocated in human cancers, including Ewing's sarcoma, leukemia, and in the case ofErg , more than half of all prostate cancers. Although evidence from mice and humans suggests thatFli-1 is required for megakaryopoiesis, and thatErg is required for normal adult hematopoietic stem cell (HSC) regulation, their precise physiological roles remain to be defined. To elucidate the relationship betweenFli-1 andErg in hematopoiesis, we conducted an analysis of mice carrying mutations in both genes. Our results demonstrate that there is a profound genetic interaction betweenFli-1 andErg . Double heterozygotes displayed phenotypes more dramatic than single heterozygotes: severe thrombocytopenia, with a significant deficit in megakaryocyte numbers and evidence of megakaryocyte dysmorphogenesis, and loss of HSCs accompanied by a reduction in the number of committed hematopoietic progenitor cells. These results illustrate an indispensable requirement for both Fli-1 and Erg in normal HSC and megakaryocyte homeostasis, and suggest these transcription factors may coregulate common target genes.