MYC target gene transactivation is associated with increased histone lysine acetylation, which is bound by bromodomain and extraterminal (BET) family proteins that in turn recruit transcriptional activators. Deregulation of MYC signalling seems to be a unifying feature of multiple myeloma; so, Delmore, Issa and colleagues assessed the expression of the BET family in multiple myeloma gene expression data sets and patient samples. They found that BRD4 expression correlated with disease progression and was commonly overexpressed or amplified in multiple myeloma samples. Transcriptional profiling of three multiple myeloma cell lines with different alterations of MYC treated with JQ1 (a small-molecule inhibitor of BET family proteins) showed that, rather than modifying gene expression nonspecifically, only 113 genes were significantly affected. Moreover, gene expression signatures associated with MYC and E2F1, but not other multiple myeloma-associated transcription factors, were downregulated on JQ1 treatment, indicating that JQ1 selectively represses MYC transcriptional programmes. The effect on E2F1 target genes requires further investigation but may result from cell-cycle arrest or a direct effect on E2F1-mediated transactivation.
Interestingly, the expression of MYC was repressed on treatment with JQ1 or another BET inhibitor (iBET) or by BRD4 knockdown. MYC suppression was also confirmed by immunoblotting using additional multiple myeloma cell lines treated with JQ1. Importantly, they showed that BRD4 binds IgH enhancers to which MYC is juxtaposed in multiple myeloma cells, and JQ1 depletes BRD4 from these sites, indicating that BRD4 is a transcriptional co-activator of MYC.
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