Journal article
BET inhibition represses miR17-92 to drive BIM-initiated apoptosis of normal and transformed hematopoietic cells
Z Xu, PP Sharp, Y Yao, D Segal, CH Ang, SL Khaw, BJ Aubrey, J Gong, GL Kelly, MJ Herold, A Strasser, AW Roberts, WS Alexander, CJ Burns, DCS Huang, SP Glaser
Leukemia | Published : 2016
DOI: 10.1038/leu.2016.52
Abstract
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. I..
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Awarded by Leukemia and Lymphoma Society
Funding Acknowledgements
We thank JM Adams, X Bu, S Cory, M Dawson, J Feutrill and A Wilks for discussions and suggestions; JM Adams, P Bouillet, L Coultas and S Cory for gifts of reagents and mouse strains; H Ierino and C Riffkin for technical assistance; S Oliver for animal husbandry; E Tsui for histology; and Catalyst Therapeutics and SYN vertical bar thesis Med Chem for provision of compounds. This work was supported by scholarships, fellowships and grants from the Australian National Health and Medical Research Council (Research Fellowships to AWR, WSA and DCSH; Australia Fellowship to AS; Project Grant 1051235 to SPG; Program Grants 1016701 and 1016647; Independent Research Institutes Infrastructure Support Scheme Grant 9000220), the Cancer Council Victoria (grants-in-aid to SPG, AWR and DCSH), the Leukemia and Lymphoma Society (SCOR Grant 7001-13 to AS, AWR and DCSH), the China Scholarship Council (to YY), the Australian Cancer Research Foundation and a Victorian State Government Operational Infrastructure Support (OIS) Grant.