Oncogenic transcription factor Evi1 regulates hematopoietic stem cell proliferation through GATA-2 expression.
The ecotropic viral integration site-1 (Evi1) is an oncogenic transcription factor in murine and human myeloid leukemia. We herein show that Evi1 is predominantly expressed in hematopoietic stem cells (HSCs) in embryos and adult bone marrows, suggesting a physiological role of Evi1 in HSCs. We therefore investigate the role and authentic target genes of Evi1 in hematopoiesis using Evi1-/- mice, which die at embryonic day 10.5. HSCs in Evi1-/- embryos are markedly decreased in numbers in vivo with defective self-renewing proliferation and repopulating capacity. Notably, expression rate of GATA-2 mRNA, which is essential for proliferation of definitive HSCs, is profoundly reduced in HSCs of Evi1-/- embryos. Restoration of the Evi1 or GATA-2 expression in Evi1-/- HSCs could prevent the failure of in vitro maintenance and proliferation of HSC through upregulation of GATA-2 expression. An analysis of the GATA-2 promoter region revealed that Evi1 directly binds to GATA-2 promoter as an enhancer. Our results reveal that GATA-2 is presumably one of critical targets for Evi1 and that transcription factors regulate the HSC pool hierarchically.
Yuasa
Hiromi
H
Department of Cell Differentiation, The Sakaguchi Laboratory, School of Medicine, Keio University, Tokyo, Japan.
Oike
Yuichi
Y
Iwama
Atsushi
A
Nishikata
Ichiro
I
Sugiyama
Daisuke
D
Perkins
Archibald
A
Mucenski
Michael L
ML
Suda
Toshio
T
Morishita
Kazuhiro
K
D042683:Angiopoietin-1 / Q000096:biosynthesis / Q000235:genetics; D042702:Angiopoietin-2 / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D001808:Blood Vessels / Q000196:embryology; D001853:Bone Marrow / Q000378:metabolism; D002455:Cell Division; D002478:Cells, Cultured / Q000166:cytology / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D050989:GATA2 Transcription Factor; D018507:Gene Expression Regulation, Developmental; D006410:Hematopoiesis / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006413:Hematopoietic System / Q000196:embryology; D006801:Humans; D000074008:MDS1 and EVI1 Complex Locus Protein; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000235:genetics / Q000502:physiology; D011401:Promoter Regions, Genetic; D011519:Proto-Oncogenes / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D042787:Receptor, TIE-2 / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D015017:Yolk Sac / Q000098:blood supply
D042683:Angiopoietin-1; D042702:Angiopoietin-2; D004268:DNA-Binding Proteins; D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human; C494712:Gata2 protein, mouse; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; C499305:Mecom protein, mouse; D012333:RNA, Messenger; D014157:Transcription Factors; D042787:Receptor, TIE-2