Dual Requirement for the ETS Transcription Factors Fli-1 and Erg in Hematopoietic Stem Cells and the Megakaryocyte Lineage

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2009 Aug 12

PMID 19666492

Citations 46

Authors

Elizabeth A 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

Affiliations

Soon will be listed here.

Abstract

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 of Erg, more than half of all prostate cancers. Although evidence from mice and humans suggests that Fli-1 is required for megakaryopoiesis, and that Erg is required for normal adult hematopoietic stem cell (HSC) regulation, their precise physiological roles remain to be defined. To elucidate the relationship between Fli-1 and Erg in hematopoiesis, we conducted an analysis of mice carrying mutations in both genes. Our results demonstrate that there is a profound genetic interaction between Fli-1 and Erg. 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.

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