TY - JOUR
T1 - BET bromodomain inhibition as a therapeutic strategy to target c-Myc
AU - Delmore, Jake E.
AU - Issa, Ghayas C.
AU - Lemieux, Madeleine E.
AU - Rahl, Peter B.
AU - Shi, Junwei
AU - Jacobs, Hannah M.
AU - Kastritis, Efstathios
AU - Gilpatrick, Timothy
AU - Paranal, Ronald M.
AU - Qi, Jun
AU - Chesi, Marta
AU - Schinzel, Anna C.
AU - McKeown, Michael R.
AU - Heffernan, Timothy P.
AU - Vakoc, Christopher R.
AU - Bergsagel, P. Leif
AU - Ghobrial, Irene M.
AU - Richardson, Paul G.
AU - Young, Richard A.
AU - Hahn, William C.
AU - Anderson, Kenneth C.
AU - Kung, Andrew L.
AU - Bradner, James E.
AU - Mitsiades, Constantine S.
N1 - Funding Information:
We are grateful to S. Lowe for sharing unpublished information; A. Azab, D. McMillin, C. Ott, and A. Roccaro for technical support; E. Fox for microarray data; J. Daley and S. Lazo-Kallanian for flow cytometry; the MMRF, MMRC, and Broad Institute for establishing the MM Genomics Portal ( http://www.broadinstitute.org/mmgp/ ). This research was supported by NIH-K08CA128972 (J.E.B.), NIH-R01CA050947 (C.S.M.), NIH-R01HG002668 (R.A.Y.), and NIH-R01CA46455 (R.A.Y.); the Chambers Medical Foundation (P.G.R., C.S.M.); the Stepanian Fund for Myeloma Research (P.G.R., C.S.M.); and the Richard J. Corman Foundation (P.G.R., C.S.M.); an American Cancer Society Postdoctoral Fellowship, 120272-PF-11-042-01-DMC (P.B.R.); the Burroughs-Wellcome Fund, the Smith Family Award, the Damon-Runyon Cancer Research Foundation, and the MMRF (to J.E.B.).
PY - 2011/9/16
Y1 - 2011/9/16
N2 - 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. PaperFlick:
AB - 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. PaperFlick:
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U2 - 10.1016/j.cell.2011.08.017
DO - 10.1016/j.cell.2011.08.017
M3 - Article
C2 - 21889194
AN - SCOPUS:80052955256
SN - 0092-8674
VL - 146
SP - 904
EP - 917
JO - Cell
JF - Cell
IS - 6
ER -