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  • The EMBO Journal (2005) 24, 1976 - 1987
  • doi:10.1038/sj.emboj.7600679

Published online: 12 May 2005

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

Hiromi Yuasa1,7, Yuichi Oike1,7, Atsushi Iwama2, Ichiro Nishikata3, Daisuke Sugiyama4, Archibald Perkins5, Michael L Mucenski6, Toshio Suda1 and Kazuhiro Morishita3

  1. Department of Cell Differentiation, The Sakaguchi Laboratory, School of Medicine, Keio University, Tokyo, Japan
  2. Department of Cellular and Molecular Biology, Graduate School of Medicine, Chiba University, Chiba, Japan
  3. Department of Biochemistry, Medical College, University of Miyazaki, Miyazaki, Japan
  4. Division of Cellular Therapy, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
  5. Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
  6. Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
  7. These authors contributed equally to this work

Correspondence to:

Yuichi Oike, Department of Cell Differentiation, The Sakaguchi Laboratory, School of Medicine, Keio University, Tokyo, Japan. Tel.: +81 3 5363 3475; Fax: +81 3 5363 3474; E-mail: oike@sc.itc.keio.ac.jp

Toshio Suda, Department of Cell Differentiation, The Sakaguchi Laboratory, School of Medicine, Keio University, Tokyo, Japan. Tel.: +81 3 5363 3475; Fax: +81 3 5363 3474; E-mail: sudato@sc.itc.keio.ac.jp

Kazuhiro Morishita, Department of Biochemistry, Faculty of Medicine, Miyazaki Medical College, University of Miyazaki, 5200 Kihara, Miyazaki 889-1692, Japan. Tel.: +81 3 5363 3473; Fax: +81 3 5363 3474; E-mail: kmorishi@med.miyazaki-u.ac.jp

Received 19 July 2004; Accepted 21 April 2005

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.

  • Keywords:

    • angiopoiesis,
    • Evi1,
    • GATA-2,
    • hematopoiesis