Massachusetts Institute of Technology. Department of Biology, Young, Richard A., Delmore, Jake E., Issa, Ghayas C., Lemieux, Madeleine E., Rahl, Peter B., Shi, Junwei, Jacobs, Hannah M., Kastritis, Efstathios, Gilpatrick, Timothy, Paranal, Ronald M., Qi, Jun, Chesi, Marta, Schinzel, Anna C., McKeown, Michael R., Heffernan, Timothy P., Vakoc, Christopher R., Bergsagel, P. Leif, Ghobrial, Irene M., Richardson, Paul G., Hahn, William C., Anderson, Kenneth C., Kung, Andrew L., Bradner, James E., Mitsiades, Constantine S., Massachusetts Institute of Technology. Department of Biology, Young, Richard A., Delmore, Jake E., Issa, Ghayas C., Lemieux, Madeleine E., Rahl, Peter B., Shi, Junwei, Jacobs, Hannah M., Kastritis, Efstathios, Gilpatrick, Timothy, Paranal, Ronald M., Qi, Jun, Chesi, Marta, Schinzel, Anna C., McKeown, Michael R., Heffernan, Timothy P., Vakoc, Christopher R., Bergsagel, P. Leif, Ghobrial, Irene M., Richardson, Paul G., Hahn, William C., Anderson, Kenneth C., Kung, Andrew L., Bradner, James E., and Mitsiades, Constantine S.
MYC contributes to the pathogenesis of a majority of human cancers, yet strategies to modulate the function of the c-Myc oncoprotein do not exist. Toward this objective, we have targeted MYC transcription by interfering with chromatin-dependent signal transduction to RNA polymerase, specifically by inhibiting the acetyl-lysine recognition domains (bromodomains) of putative coactivator proteins implicated in transcriptional initiation and elongation. Using a selective small-molecule bromodomain inhibitor, JQ1, we identify BET bromodomain proteins as regulatory factors for c-Myc. BET inhibition by JQ1 downregulates MYC transcription, followed by genome-wide downregulation of Myc-dependent target genes. In experimental models of multiple myeloma, a Myc-dependent hematologic malignancy, JQ1 produces a potent antiproliferative effect associated with cell-cycle arrest and cellular senescence. Efficacy of JQ1 in three murine models of multiple myeloma establishes the therapeutic rationale for BET bromodomain inhibition in this disease and other malignancies characterized by pathologic activation of c-Myc., National Institutes of Health (U.S.) (NIH-K08CA128972), National Institutes of Health (U.S.) (NIH-R01CA050947), National Institutes of Health (U.S.) (NIH-R01HG002668), National Institutes of Health (U.S.) (NIH-R01CA46455), Massachusetts General Hospital (Chambers Medical Foundation), Harvard University (Stepanian Fund for Myeloma Research), Harvard University (Richard J. Corman Foundation), American Cancer Society (Postdoctoral Fellowship, 120272-PF-11-042-01-DMC), Burroughs Wellcome Fund, Richard and Susan Smith Family Foundation, Damon Runyon Cancer Research Foundation, Multiple Myeloma Research Foundation