title: BET inhibition represses miR17-92 to drive BIM-initiated apoptosis of normal and transformed hematopoietic cells.
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.
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Z
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: P P
authors.initials: PP
authors.lastname: Sharp
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.|School of Medicine, Tsinghua University, Beijing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: D
authors.initials: D
authors.lastname: Segal
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: C H
authors.initials: CH
authors.lastname: Ang
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.|Children's Cancer Centre, The Royal Children's Hospital, Melbourne, Victoria, Australia.
authors.forename: S L
authors.initials: SL
authors.lastname: Khaw
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.|Department of Clinical Haematology and Bone Marrow Transplantation, The Royal Melbourne Hospital, Melbourne, Victoria, Australia.
authors.forename: B J
authors.initials: BJ
authors.lastname: Aubrey
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Gong
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: G L
authors.initials: GL
authors.lastname: Kelly
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: M J
authors.initials: MJ
authors.lastname: Herold
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Strasser
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.|Department of Clinical Haematology and Bone Marrow Transplantation, The Royal Melbourne Hospital, Melbourne, Victoria, Australia.|Victorian Comprehensive Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: A W
authors.initials: AW
authors.lastname: Roberts
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: W S
authors.initials: WS
authors.lastname: Alexander
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: C J
authors.initials: CJ
authors.lastname: Burns
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: D C S
authors.initials: DC
authors.lastname: Huang
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: S P
authors.initials: SP
authors.lastname: Glaser
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001381:Azepines / Q000494:pharmacology*; D000072224:Bcl-2-Like Protein 11 / Q000502:physiology*; D018797:Cell Cycle Proteins; D002460:Cell Line; D002461:Cell Line, Transformed; D004195:Disease Models, Animal; D006413:Hematopoietic System / Q000166:cytology; D049690:History, Ancient; D006801:Humans; D008223:Lymphoma / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000037:antagonists & inhibitors*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors; D062085:RNA, Long Noncoding; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D014230:Triazoles / Q000494:pharmacology*; D000092468:Bromodomain Containing Proteins
chemical_list: D001381:Azepines; D000072224:Bcl-2-Like Protein 11; D018797:Cell Cycle Proteins; D035683:MicroRNAs; D009687:Nuclear Proteins; D062085:RNA, Long Noncoding; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C568997:MIR17HG, human