Growth Factor Independence 1 Protects Hematopoietic Stem Cells Against Apoptosis but Also Prevents the Development of a Myeloproliferative-Like Disease§

Authors

  • Cyrus Khandanpour,

    1. Institut de recherches cliniques de Montréal (IRCM)Université de Montréal, Montréal, Quebec, Canada
    2. Département de microbiologie et immunologie, Université de Montréal, Montréal, Quebec, Canada
    3. Institut für Zellbiologie (Tumorforschung)Universitätsklinikum Essen, Essen, Germany
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    • C. Khandanpour and C. Kosan contributed equally to this work.

  • Christian Kosan,

    1. Institut de recherches cliniques de Montréal (IRCM)Université de Montréal, Montréal, Quebec, Canada
    2. Institut für Zellbiologie (Tumorforschung)Universitätsklinikum Essen, Essen, Germany
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    • C. Khandanpour and C. Kosan contributed equally to this work.

  • Marie-Claude Gaudreau,

    Corresponding author
    1. Institut de recherches cliniques de Montréal (IRCM)Université de Montréal, Montréal, Quebec, Canada
    2. Département de microbiologie et immunologie, Université de Montréal, Montréal, Quebec, Canada
    • Beijing Ditan Hospital, 8 Jingshundongjie, Beijing 100015, China
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  • Ulrich Dührsen,

    Corresponding author
    1. Klinik für Hämatologie, Universitätsklinikum Essen, Essen, Germany
    • Beijing Ditan Hospital, 8 Jingshundongjie, Beijing 100015, China
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  • Josée Hébert,

    1. Leukemia Cell Bank of Quebec and Division of Hematology, Maisonneuve-Rosemont Hospital Montréal, Montréal, Quebec, Canada
    2. Department of Medicine, University of Montreal, Montreal, Quebec, Canada
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  • Hui Zeng,

    Corresponding author
    1. Institut für Zellbiologie (Tumorforschung)Universitätsklinikum Essen, Essen, Germany
    2. Institute of Infectious diseases, Capital Medical University, Beijing, China
    3. Beijing Ditan Hospital, Beijing, China
    • Beijing Ditan Hospital, 8 Jingshundongjie, Beijing 100015, China
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  • Tarik Möröy

    Corresponding author
    1. Institut de recherches cliniques de Montréal (IRCM)Université de Montréal, Montréal, Quebec, Canada
    2. Département de microbiologie et immunologie, Université de Montréal, Montréal, Quebec, Canada
    3. Institut für Zellbiologie (Tumorforschung)Universitätsklinikum Essen, Essen, Germany
    4. Zentrum für Medizinische Biotechnologie (ZMB), Universität Duisburg-Essen, Essen, Germany
    • Institut de recherches cliniques de Montréal (IRCM), 110 Avenue des Pins Ouest, Montréal, Québec, Canada H2W 1R7
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    • Telephone: 514-987-5501; Fax: 514-987-5679


  • Author contributions: C. Khandanpour and C. Kosan: design of experiments, collection, interpretation and analysis of data, manuscript writing; M.-C.G. and U.D.: collection, interpretation, and analysis of data; H.Z.: design of experiments, interpretation, and analysis of data; J.H.: karyotype analysis; T.M.: conception of work, design of experiments, interpretation and analysis of data, writing of manuscript, financial support, and funding.

  • Disclosure of potential conflicts of interest is found at the end of this article.

  • §

    First published online in STEM CELLSEXPRESS December 9, 2010.

  • Telephone: +86-10-84322621. Fax: +86-10-84322606

Abstract

The regulation of gene transcription is elementary for the function of hematopoietic stem cells (HSCs). The transcriptional repressor growth factor independence 1 (Gfi1) restricts HSC proliferation and is essential to maintain their self-renewal capacity and multipotency after transplantation. In addition, Gfi1−/− HSCs are severely compromised in their ability to compete with wild-type (wt) HSCs after transplantation. We now report that Gfi1 protects HSCs against stress-induced apoptosis, probably, by repressing the proapoptotic target gene Bax, since irradiated Gfi1−/− HSCs display higher expression of Bax and show a higher rate of apoptosis than wt HSCs. This protective function of Gfi1 appears to be functionally relevant since Gfi1−/− HSCs that express Bcl-2, which antagonizes the effects of Bax, regain their ability to self renew and to initiate multilineage differentiation after transplantation. Surprisingly, Gfi1−/−xBcl-2 transgenic mice also show a strong, systemic expansion of Mac-1+Gr-1 myeloid cells in bone marrow and peripheral lymphoid organs. These cells express high levels of the proleukemogenic transcription factor Hoxa9 and, in older mice, appear as atypical monocytoid-blastoid cells in the peripheral blood. As a result of this massive expansion of myeloid cells, all Gfi1−/−xBcl-2 mice eventually succumb to a myeloproliferative-like disease resembling a preleukemic state. In summary, our data demonstrate that Gfi1's ability to protect against apoptosis is essential for HSC function. In addition, our finding show that Gfi1 prevents the development of myeloproliferative diseases and provides evidence how Gfi1 deficiency could be linked to myeloid leukemia. STEM CELLS 2011;29:376–385

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