TY  - JOUR
AU  - Delbridge, ARD
AU  - Aubrey, BJ
AU  - Hyland, C
AU  - Bernardini, JP
AU  - Di Rago, L
AU  - Garnier, J-M
AU  - Lessene, G
AU  - Strasser, A
AU  - Alexander, WS
AU  - Grabow, S
Y2  - 2021/02/04
Y1  - 2017/07/01
SN  - 2041-4889
UR  - http://hdl.handle.net/11343/259668
AB  - 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.
LA  - English
PB  - NATURE PUBLISHING GROUP
T1  - The BH3-only proteins BIM and PUMA are not critical for the reticulocyte apoptosis caused by loss of the pro-survival protein BCL-XL
DO  - 10.1038/cddis.2017.304
IS  - Cell Death and Disease
VL  - 8
IS  - 7
L1  - /bitstream/handle/11343/259668/PMC5550852.pdf?sequence=1&isAllowed=y
ER  -