The BH3-only proteins BIM and PUMA are not critical for the reticulocyte apoptosis caused by loss of the pro-survival protein BCL-XL
AuthorDelbridge, ARD; Aubrey, BJ; Hyland, C; Bernardini, JP; Di Rago, L; Garnier, J-M; Lessene, G; Strasser, A; Alexander, WS; Grabow, S
Source TitleCell Death and Disease
PublisherNATURE PUBLISHING GROUP
University of Melbourne Author/sGrabow, Stephanie; Lessene, Guillaume; Alexander, Warren; Strasser, Andreas; Delbridge, Alex; Garnier, Jean-Marc; Bernardini, Jonathan; Aubrey, Brandon
AffiliationMedical Biology (W.E.H.I.)
Document TypeJournal Article
CitationsDelbridge, 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 StatusOpen Access
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.
- Click on "Export Reference in RIS Format" and choose "open with... Endnote".
- Click on "Export Reference in RIS Format". Login to Refworks, go to References => Import References