title: BET Inhibition Induces Apoptosis in Aggressive B-Cell Lymphoma via Epigenetic Regulation of BCL-2 Family Members.
abstract: Targeting BET bromodomain proteins using small molecules is an emerging anticancer strategy with clinical evaluation of at least six inhibitors now underway. Although MYC downregulation was initially proposed as a key mechanistic property of BET inhibitors, recent evidence suggests that additional antitumor activities are important. Using the Eμ-Myc model of B-cell lymphoma, we demonstrate that BET inhibition with JQ1 is a potent inducer of p53-independent apoptosis that occurs in the absence of effects on Myc gene expression. JQ1 skews the expression of proapoptotic (Bim) and antiapoptotic (BCL-2/BCL-xL) BCL-2 family members to directly engage the mitochondrial apoptotic pathway. Consistent with this, Bim knockout or Bcl-2 overexpression inhibited apoptosis induction by JQ1. We identified lymphomas that were either intrinsically resistant to JQ1-mediated death or acquired resistance following in vivo exposure. Strikingly, in both instances BCL-2 was strongly upregulated and was concomitant with activation of RAS pathways. Eμ-Myc lymphomas engineered to express activated Nras upregulated BCL-2 and acquired a JQ1 resistance phenotype. These studies provide important information on mechanisms of apoptosis induction and resistance to BET-inhibition, while providing further rationale for the translation of BET inhibitors in aggressive B-cell lymphomas. Mol Cancer Ther; 15(9); 2030-41. ©2016 AACR.
authors.affiliation: Gene Regulation Laboratory, Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Hogg
authors.affiliation: Gene Regulation Laboratory, Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: Andrea
authors.initials: A
authors.lastname: Newbold
authors.affiliation: Gene Regulation Laboratory, Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: Stephin J
authors.initials: SJ
authors.lastname: Vervoort
authors.affiliation: Gene Regulation Laboratory, Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: Leonie A
authors.initials: LA
authors.lastname: Cluse
authors.affiliation: Gene Regulation Laboratory, Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Martin
authors.affiliation: Gene Regulation Laboratory, Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. Monash Hematology, Monash Health, Clayton, Victoria, Australia.
authors.forename: Gareth P
authors.initials: GP
authors.lastname: Gregory
authors.affiliation: Gene Regulation Laboratory, Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Marcus
authors.initials: M
authors.lastname: Lefebure
authors.affiliation: Gene Regulation Laboratory, Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: Eva
authors.initials: E
authors.lastname: Vidacs
authors.affiliation: Gene Regulation Laboratory, Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Tothill
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.affiliation: Gene Regulation Laboratory, Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. Monash Hematology, Monash Health, Clayton, Victoria, Australia. School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia. ricky.johnstone@petermac.org jake.shortt@monashhealth.org.
authors.forename: Jake
authors.initials: J
authors.lastname: Shortt
authors.affiliation: Gene Regulation Laboratory, Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. ricky.johnstone@petermac.org jake.shortt@monashhealth.org.
authors.forename: Ricky W
authors.initials: RW
authors.lastname: Johnstone
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D001381:Azepines / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D051379:Mice; D005810:Multigene Family; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C561695:(+)-JQ1 compound; D001381:Azepines; D019253:Proto-Oncogene Proteins c-bcl-2; D014230:Triazoles; D016159:Tumor Suppressor Protein p53; D016283:Proto-Oncogene Proteins p21(ras)