BET bromodomain inhibition as a therapeutic strategy to target c-Myc

Jake E. Delmore, Ghayas C. Issa, Madeleine E. Lemieux, Peter B. Rahl, Junwei Shi, Hannah M. Jacobs, Efstathios Kastritis, Timothy Gilpatrick, Ronald M. Paranal, Jun Qi, Marta Chesi, Anna C. Schinzel, Michael R. McKeown, Timothy P. Heffernan, Christopher R. Vakoc, P. Leif Bergsagel, Irene M. Ghobrial, Paul G. Richardson, Richard A. Young, William C. HahnKenneth C. Anderson, Andrew L. Kung, James E. Bradner, Constantine S. Mitsiades

Research output: Contribution to journalArticle

1612 Scopus citations

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:

Original languageEnglish (US)
Pages (from-to)904-917
Number of pages14
JournalCell
Volume146
Issue number6
DOIs
StatePublished - Sep 16 2011

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Delmore, J. E., Issa, G. C., Lemieux, M. E., Rahl, P. B., Shi, J., 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. L., Ghobrial, I. M., Richardson, P. G., Young, R. A., ... Mitsiades, C. S. (2011). BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell, 146(6), 904-917. https://doi.org/10.1016/j.cell.2011.08.017