Abstract
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.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiopoietin-1 / biosynthesis
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Angiopoietin-1 / genetics
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Angiopoietin-2 / biosynthesis
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Angiopoietin-2 / genetics
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Animals
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Blood Vessels / embryology
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Bone Marrow / metabolism
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Cell Division
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Cells, Cultured / cytology
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Cells, Cultured / metabolism
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DNA-Binding Proteins / biosynthesis*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology*
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GATA2 Transcription Factor
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Gene Expression Regulation, Developmental*
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Hematopoiesis / genetics
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Hematopoietic Stem Cells / cytology*
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Hematopoietic Stem Cells / metabolism
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Hematopoietic System / embryology
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Humans
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MDS1 and EVI1 Complex Locus Protein
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Mice
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Mice, Knockout
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Neovascularization, Physiologic / genetics
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Neovascularization, Physiologic / physiology
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Promoter Regions, Genetic
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Proto-Oncogenes / genetics
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Proto-Oncogenes / physiology*
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RNA, Messenger / biosynthesis
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Receptor, TIE-2 / biosynthesis
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Receptor, TIE-2 / genetics
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Transcription Factors / biosynthesis*
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Transcription Factors / genetics
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Transcription Factors / physiology*
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Transcription, Genetic*
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Yolk Sac / blood supply
Substances
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Angiopoietin-1
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Angiopoietin-2
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DNA-Binding Proteins
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GATA2 Transcription Factor
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GATA2 protein, human
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Gata2 protein, mouse
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MDS1 and EVI1 Complex Locus Protein
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MECOM protein, human
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Mecom protein, mouse
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RNA, Messenger
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Transcription Factors
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Receptor, TIE-2