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    The BH3-only proteins BIM and PUMA are not critical for the reticulocyte apoptosis caused by loss of the pro-survival protein BCL-XL

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    7
    Author
    Delbridge, ARD; Aubrey, BJ; Hyland, C; Bernardini, JP; Di Rago, L; Garnier, J-M; Lessene, G; Strasser, A; Alexander, WS; Grabow, S
    Date
    2017-07-01
    Source Title
    Cell Death and Disease
    Publisher
    NATURE PUBLISHING GROUP
    University of Melbourne Author/s
    Grabow, Stephanie; Lessene, Guillaume; Alexander, Warren; Strasser, Andreas; Delbridge, Alex; Garnier, Jean-Marc; Bernardini, Jonathan; Aubrey, Brandon
    Affiliation
    Medical Biology (W.E.H.I.)
    Metadata
    Show full item record
    Document Type
    Journal Article
    Citations
    Delbridge, A. R. D., Aubrey, B. J., Hyland, C., Bernardini, J. P., Di Rago, L., Garnier, J. -M., Lessene, G., Strasser, A., Alexander, W. S. & Grabow, S. (2017). The BH3-only proteins BIM and PUMA are not critical for the reticulocyte apoptosis caused by loss of the pro-survival protein BCL-XL. CELL DEATH & DISEASE, 8 (7), https://doi.org/10.1038/cddis.2017.304.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/259668
    DOI
    10.1038/cddis.2017.304
    Abstract
    Anaemia is a major global health problem arising from diverse causes and for which improved therapeutic strategies are needed. Erythroid cells can undergo apoptotic cell death and loss of pro-survival BCL-XL is known to trigger apoptosis during late-stage erythroid development. However, the mechanism by which loss or pharmacological blockade of BCL-XL leads to erythroid cell apoptosis remains unclear. Here we sought to identify the precise stage of erythropoiesis that depends on BCL-XL. We also tested whether deficiency of BIM or PUMA, the two main pro-apoptotic antagonists of BCL-XL, could prevent reticulocyte death and anaemia caused by BCL-XL loss. Using an in vivo mouse model of tamoxifen-inducible Bclx gene deletion and in vitro assays with a BCL-XL-selective inhibitor, we interrogated each stage of erythrocyte differentiation for BCL-XL dependency. This revealed that reticulocytes, but not orthochromatic erythroblasts, require BCL-XL for their survival. Surprisingly, concurrent loss of BIM or PUMA had no significant impact on the development of anemia following acute BCL-XL deletion in vivo. However, analysis of mixed bone marrow chimaeric mice revealed that loss of PUMA, but not loss of BIM, partially alleviated impaired erythropoiesis caused by BCL-XL deficiency. Insight into how the network of pro-survival and pro-apoptotic proteins works will assist the development of strategies to mitigate the effects of abnormal cell death during erythropoiesis and prevent anaemia in patients treated with BCL-XL-specific BH3-mimetic drugs.

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