Haematopoietic stem cell survival and transplantation efficacy is limited by the BH3-only proteins Bim and Bmf

Authors

  • Verena Labi,

    Corresponding author
    1. Division of Developmental Immunology, Biocenter, Innsbruck Medical University, Innsbruck, Austria
    2. Present address: Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany
    • Verena Labi, Tel: +43 512 9003 70380; Fax: +43 512 9003 73964

      Miriam Erlacher, Tel: +49 761 27043010; Fax: +49 761 27046230

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    • These authors contributed equally to this work.

  • Daniela Bertele,

    1. Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University Hospital of Freiburg, Freiburg, Germany
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    • These authors contributed equally to this work.

  • Claudia Woess,

    1. Division of Developmental Immunology, Biocenter, Innsbruck Medical University, Innsbruck, Austria
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  • Denise Tischner,

    1. Division of Developmental Immunology, Biocenter, Innsbruck Medical University, Innsbruck, Austria
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  • Florian J. Bock,

    1. Division of Developmental Immunology, Biocenter, Innsbruck Medical University, Innsbruck, Austria
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  • Sven Schwemmers,

    1. Section of Molecular Hematology, Department of Hematology/Oncology, University Hospital of Freiburg, Freiburg, Germany
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  • Heike L. Pahl,

    1. Section of Molecular Hematology, Department of Hematology/Oncology, University Hospital of Freiburg, Freiburg, Germany
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  • Stephan Geley,

    1. Division of Molecular Pathophysiology, Biocenter, Innsbruck Medical University, Innsbruck, Austria
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  • Mirjam Kunze,

    1. Department of Obstetrics and Gynecology, University Hospital Freiburg, Freiburg, Germany
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  • Charlotte M. Niemeyer,

    1. Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University Hospital of Freiburg, Freiburg, Germany
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  • Andreas Villunger,

    1. Division of Developmental Immunology, Biocenter, Innsbruck Medical University, Innsbruck, Austria
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  • Miriam Erlacher

    Corresponding author
    1. Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University Hospital of Freiburg, Freiburg, Germany
    • Verena Labi, Tel: +43 512 9003 70380; Fax: +43 512 9003 73964

      Miriam Erlacher, Tel: +49 761 27043010; Fax: +49 761 27046230

    Search for more papers by this author

Abstract

Anti-apoptotic Bcl-2 family members are critical for the regulation of haematopoietic stem and progenitor cell (HSPC) survival. Little is known about the role of their pro-apoptotic antagonists, i.e. ‘BH3-only’ proteins, in this cell compartment. Based on the analysis of cytokine deprivation-induced changes in mRNA expression levels of Bcl-2 family proteins, we determined the consequences of BH3-only protein depletion on HSPC survival in culture and, for selected candidates, on engraftment in vivo. Thereby, we revealed a critical role for Bim and Bmf as regulators of HSPC dynamics both during early engraftment and long-term reconstitution. HSPCs derived from wild-type donors were readily displaced by Bim- or Bmf-deficient or Bcl-2-overexpressing HSPCs as early as 10 days after engraftment. Moreover, in the absence of Bim, significantly lower numbers of transplanted HSPCs were able to fully engraft radio-depleted recipients. Finally, we provide proof of principle that RNAi-based reduction of BIM or BMF, or overexpression of BCL-2 in human CD34+ cord blood cells may be an attractive therapeutic option to increase stem cell survival and transplantation efficacy.

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