BET Bromodomain Inhibition as a Therapeutic Strategy to Target c-Myc

Delmore, J. E., Issa, G. C., Lemieux, M. E., Rahl, P. B., Shi, J. W., Jacobs, H. M., Kastritis, E., Gilpatrick, T., Paranal, R. M., Qi, J., Chesi, M., Schinzel, A. C., McKeown, M. R., Heffernan, T. P., Vakoc, C. R., Bergsagel, P.  , Ghobrial, I. M., Richardson, P. G., Young, R. A., Hahn, W. C., Anderson, K. C., Kung, A. L., Bradner, J. E., Mitsiades, C. S. (September 2011) BET Bromodomain Inhibition as a Therapeutic Strategy to Target c-Myc. Cell, 146 (6). pp. 904-917. ISSN 00928674 (ISSN)

URL: http://www.ncbi.nlm.nih.gov/pubmed/21889194
DOI: 10.1016/j.cell.2011.08.017

Abstract

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: . Display Omitted. © 2011 Elsevier Inc. All rights reserved.

Item Type: Paper
Subjects: diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > transcription
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > RNA polymerase
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > acetyl-lysine recognition domain
organism description > animal > mammal > primates > hominids > human
CSHL Authors:
Communities: CSHL Cancer Center Shared Resources > DNA Sequencing Service
CSHL Cancer Center Shared Resources > Flow Cytometry Service
CSHL labs > Vakoc lab
CSHL Cancer Center Program > Gene Regulation and Cell Proliferation
Depositing User: CSHL Librarian
Date: 16 September 2011
Date Deposited: 09 Nov 2011 20:05
Last Modified: 06 Oct 2015 20:23
PMCID: PMC3187920
Related URLs:
URI: http://repository.cshl.edu/id/eprint/15654

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