journal contribution
posted on 2023-04-03, 14:42 authored by Simon J. Hogg, Andrea Newbold, Stephin J. Vervoort, Leonie A. Cluse, Benjamin P. Martin, Gareth P. Gregory, Marcus Lefebure, Eva Vidacs, Richard W. Tothill, James E. Bradner, Jake Shortt, Ricky W. Johnstone Supplementary Methods, Supplementary References, Supplementary Figure 1 - in vitro analysis of various BET inhibitors against Eu-myc lymphoma cells and effect of JQ1 on OPM2 and OPM2/BCL2 cells; Supplementary Figure 2 - In vitro effects of JQ1 on OPM2 and OPM2/BCL2 cells; Supplementary Figure 3 - In vivo effects of JQ1 showing lack of toxicity; Supplementary Figure 4 - induction of Bim in JQ1-sensitive and JQ1-resistant Eu-myc lymphomas; Supplementary Figure 5 - Activated Ras confers resistance to JAK inhibitor and JQ1.
Funding
Leukemia Foundation of Australia
CRC
Royal Australasian College of Physicians
Arrow Bone Marrow Transplant Foundation
Eva and Les Erdi/Snowdome Foundation Victorian Cancer Agenc
NHMRC
History
ARTICLE 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.
