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Molecular targets for therapy

BET inhibition represses miR17-92 to drive BIM-initiated apoptosis of normal and transformed hematopoietic cells

Leukemia volume 30, pages 1531–1541 (2016)Cite this article

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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. 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.

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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|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.

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Author notes

  1. P P Sharp

    Present address: 7Current address: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA.,

  2. D C S Huang and S P Glaser: Joint senior authors.

Authors and Affiliations

  1. Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia

    Z Xu, P P Sharp, Y Yao, D Segal, C H Ang, S L Khaw, B J Aubrey, J Gong, G L Kelly, M J Herold, A Strasser, A W Roberts, W S Alexander, C J Burns, D C S Huang & S P Glaser

  2. Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia

    Z Xu, P P Sharp, Y Yao, D Segal, C H Ang, S L Khaw, B J Aubrey, J Gong, G L Kelly, M J Herold, A Strasser, A W Roberts, W S Alexander, C J Burns, D C S Huang & S P Glaser

  3. School of Medicine, Tsinghua University, Beijing, China

    Y Yao

  4. Children’s Cancer Centre, The Royal Children’s Hospital, Melbourne, Victoria, Australia

    S L Khaw

  5. Department of Clinical Haematology and Bone Marrow Transplantation, The Royal Melbourne Hospital, Melbourne, Victoria, Australia

    B J Aubrey & A W Roberts

  6. Victorian Comprehensive Cancer Centre, Melbourne, Victoria, Australia

    A W Roberts

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Xu, Z., Sharp, P., Yao, Y. et al. BET inhibition represses miR17-92 to drive BIM-initiated apoptosis of normal and transformed hematopoietic cells. Leukemia 30, 1531–1541 (2016). https://doi.org/10.1038/leu.2016.52

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