Oncogenic transcription factor Evi1 regulates hematopoietic stem cell proliferation through GATA-2 expression

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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.