Dual requirement for the ETS transcription factors Fli-1 and Erg in hematopoietic stem cells and the megakaryocyte lineage.
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.
Kruse
Elizabeth A
EA
Divisions of Molecular Medicine and Cancer and Haematology, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville 3052, Australia.
Loughran
Stephen J
SJ
Baldwin
Tracey M
TM
Josefsson
Emma C
EC
Ellis
Sarah
S
Watson
Dennis K
DK
Nurden
Paquita
P
Metcalf
Donald
D
Hilton
Douglas J
DJ
Alexander
Warren S
WS
Kile
Benjamin T
BT
D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D019070:Cell Lineage; D003433:Crosses, Genetic; D005786:Gene Expression Regulation; D006579:Heterozygote; D006801:Humans; D008533:Megakaryocytes / Q000166:cytology*; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D009154:Mutation; D015513:Oncogene Proteins / Q000737:chemistry*; D051789:Proto-Oncogene Protein c-fli-1 / Q000737:chemistry*; D013926:Thrombopoietin / Q000378:metabolism; D014157:Transcription Factors; D000071230:Transcriptional Regulator ERG
C531115:ERG protein, mouse; C497426:Fli1 protein, mouse; D015513:Oncogene Proteins; D051789:Proto-Oncogene Protein c-fli-1; D014157:Transcription Factors; D000071230:Transcriptional Regulator ERG; D013926:Thrombopoietin