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dc.contributor.authorDelbridge, ARD
dc.contributor.authorAubrey, BJ
dc.contributor.authorHyland, C
dc.contributor.authorBernardini, JP
dc.contributor.authorDi Rago, L
dc.contributor.authorGarnier, J-M
dc.contributor.authorLessene, G
dc.contributor.authorStrasser, A
dc.contributor.authorAlexander, WS
dc.contributor.authorGrabow, S
dc.date.accessioned2021-02-04T02:24:16Z
dc.date.available2021-02-04T02:24:16Z
dc.date.issued2017-07-01
dc.identifierpii: cddis2017304
dc.identifier.citationDelbridge, 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.
dc.identifier.issn2041-4889
dc.identifier.urihttp://hdl.handle.net/11343/259668
dc.description.abstractAnaemia 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.
dc.languageEnglish
dc.publisherNATURE PUBLISHING GROUP
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titleThe BH3-only proteins BIM and PUMA are not critical for the reticulocyte apoptosis caused by loss of the pro-survival protein BCL-XL
dc.typeJournal Article
dc.identifier.doi10.1038/cddis.2017.304
melbourne.affiliation.departmentMedical Biology (W.E.H.I.)
melbourne.affiliation.facultyMedicine, Dentistry & Health Sciences
melbourne.source.titleCell Death and Disease
melbourne.source.volume8
melbourne.source.issue7
dc.rights.licenseCC BY
melbourne.elementsid1221416
melbourne.contributor.authorGrabow, Stephanie
melbourne.contributor.authorLessene, Guillaume
melbourne.contributor.authorAlexander, Warren
melbourne.contributor.authorStrasser, Andreas
melbourne.contributor.authorDelbridge, Alex
melbourne.contributor.authorGarnier, Jean-Marc
melbourne.contributor.authorBernardini, Jonathan
melbourne.contributor.authorAubrey, Brandon
dc.identifier.eissn2041-4889
melbourne.accessrightsOpen Access


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