BET inhibition represses miR17-92 to drive BIM-initiated apoptosis of normal and transformed hematopoietic cells
- Xu, Z; Sharp, PP; Yao, Y; Segal, D; Ang, CH; Khaw, SL; Aubrey, BJ; Gong, J; Kelly, GL; Herold, MJ; Strasser, A; Roberts, AW; Alexander, WS; Burns, CJ; Huang, DC; Glaser, SP;
Publication Year 2016-03-08, Volume 30, Issue #7, Page 1531-1541
- Journal Title
- Publication Type
- Journal Article
- The BET (bromodomain and extraterminal domain) bromodomain-containing proteins, such as BRD4, are highly promising targets for treating lymphoid and myeloid malignancies. They act to modulate the expression of multiple genes that control diverse cellular processes including proliferation, survival and differentiation that are consequentially disrupted by small-molecule BET bromodomain inhibitors such as JQ1. By assessing the impact of these inhibitors on normal mouse hematopoietic cells or their transformed counterparts, we establish definitively that their cytotoxic action in vitro and in vivo relies predominantly on the activation of BAX/BAK-dependent mitochondrial (intrinsic) apoptosis. In large part, this is triggered by marked upregulation of the BH3-only protein BIM when the BET inhibitors suppress miR-17-92, a key post-transcriptional repressor of BIM expression. Thus, our study strongly suggests that mutations that permit the evasion of apoptosis (for example, BCL2 overexpression, BIM inactivation) are likely to blunt the activity of the BET bromodomain inhibitors and should be anticipated when therapy resistance develops. Strikingly, we also found that certain normal hematopoietic cells, especially those of lymphoid origin, are as prone to apoptosis induced by the BET inhibitors as their transformed counterparts, indicating that their susceptibility to BET inhibitors did not arise from oncogenic transformation.Leukemia advance online publication, 8 April 2016; doi:10.1038/leu.2016.52.
- WEHI Research Division(s)
- Chemical Biology; Cancer And Haematology; Molecular Genetics Of Cancer
- PubMed ID
- Publisher's Version
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Creation Date: 2016-04-28 02:07:02Last Modified: 2016-12-13 02:28:50