Cell 146, 904–917 (2011)

Overexpression of the transcriptional activator c-Myc is associated with cell proliferation in numerous malignancies. However, direct pharmacological inhibition of c-Myc has proven difficult. Delmore et al. now show that c-Myc activity can be downregulated in cancer cell lines through an indirect route involving the perturbation of coactivator protein recruitment to chromatin. Using expression analysis and RNA interference, the authors showed that BRD4, a member of the bromodomain and extraterminal (BET) class of transcriptional coactivators, is associated with disease progression in multiple myeloma (MM). The authors hypothesized that JQ1, a triazolodiazepine compound that specifically inhibits BET protein binding to acetyllysine-modified histones in chromatin, could be used as a chemical probe to explore the link between BET proteins and c-Myc regulation in MM. Treatment of MM cells with JQ1 disrupted the transcriptional programs downstream of c-Myc. Surprisingly, JQ1 treatment also blocked transcription of MYC itself in a dose-dependent manner. Chromatin immunoprecipitation revealed that BRD4 accumulates at immunoglobulin enhancer elements abnormally fused to the MYC gene in MM and that JQ1 can deplete these strong enhancers of BRD4. These results suggested that pharmacological inhibition of BET-chromatin interactions has the potential to block MYC-induced cell proliferation—a prediction that was validated in several mouse models of multiple myeloma.