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We provide evidence that MYC gene expression can be potently and reversibly abrogated by BET bromodomains inhibitors. Transcriptional silencing of MYC is coincident with release of BET proteins from the MYC locus, indicating that BET proteins directly regulate MYC gene expression. Although BET inhibitors influence the expression of an assortment of genes, the MYC transcriptome heavily dominates the gene expression changes observed upon BET-bromodomain inhibition. The MYC gene is translocated in all patients with BL and a significant fraction of patients with multiple myeloma or diffuse large B-cell lymphoma (19). BL is well established to depend on the functions of MYC (15, 19). We observed that several cell lines harboring MYC translocations are sensitive to BET inhibitors as measured by both transcriptional effects and apoptotic responses (Fig. 1, Fig. S2, and Fig. S3), perhaps reflecting their degree of MYC addiction (20). Apart from the special case of midline carcinoma, we have yet to observe a cell type that is sensitive to BET inhibitors without down-regulation of MYC (Fig. S6A). However, MYC reduction did not always correlate with a cell proliferation phenotype in vitro. For example, MYC protein was significantly reduced in the breast cancer cell line MDA-MB-231, which nevertheless grew normally upon administration of (+)-JQ1 (Fig. 1A and Fig. S3B). Previous studies have indicated that the in vitro proliferation of the MDA-MB-231 cell line is only mildly affected by a severe reduction of MYC protein by shRNA (21). To corroborate this observation, we infected MDA-MB-231 cells with four different shRNAs that knockdown MYC mRNA and assessed their effect on proliferation. As shown in Fig. S6B, MDA-MB-231 cells are not phenotypically sensitive to MYC knockdown by shRNA at comparable mRNA knockdown levels to (+)-JQ1–mediated suppression of MYC. No gross toxicity was observed upon high-dose treatment of BET inhibitors in this MYC-insensitive cell line, revealing no marked, general MYC-independent effects on cellular viability in this setting. Suppression of MYC by BET inhibitors was not observed in every cell line tested, and the degree of MYC silencing also varied at the time points tested. It is possible that variation in the permeability and efflux of BET inhibitors across cell lines contributes to some of these observations. Conceptually, it will be important to elucidate in detail the chromatin or regulatory contexts that define MYC sensitivity to BET inhibitors. These regulatory features may ultimately identify the patients who will respond best to this class of small molecule inhibitors.

http://www.pnas.org/content/108/40/16669.full