Title |
BET Inhibition Induces Apoptosis in Aggressive B-Cell Lymphoma via Epigenetic Regulation of BCL-2 Family Members
|
---|---|
Published in |
Molecular Cancer Therapeutics, September 2016
|
DOI | 10.1158/1535-7163.mct-15-0924 |
Pubmed ID | |
Authors |
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 |
Abstract |
Targeting BET bromodomain proteins utilizing small molecules in an emerging anti-cancer strategy with clinical evaluation of at least six inhibitors now underway. While MYC downregulation was initially proposed as a key mechanistic property of BET inhibitors, recent evidence suggests that additional anti-tumor 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 pro-apoptotic (Bim) and anti-apoptotic (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 apoptosis induction and resistance to BET-inhibition, while providing further rationale for the translation of BET inhibitors in aggressive B-cell lymphomas. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
France | 1 | 50% |
Unknown | 1 | 50% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 2 | 100% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 49 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 11 | 22% |
Student > Ph. D. Student | 9 | 18% |
Student > Bachelor | 5 | 10% |
Student > Master | 5 | 10% |
Student > Doctoral Student | 3 | 6% |
Other | 6 | 12% |
Unknown | 10 | 20% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 20 | 41% |
Medicine and Dentistry | 8 | 16% |
Agricultural and Biological Sciences | 4 | 8% |
Pharmacology, Toxicology and Pharmaceutical Science | 2 | 4% |
Chemistry | 2 | 4% |
Other | 2 | 4% |
Unknown | 11 | 22% |