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

被引：2604

作者：

Delmore, Jake E. ^{[1
]}

Issa, Ghayas C. ^{[1
]}

Lemieux, Madeleine E. ^{[2
,3
]}

Rahl, Peter B. ^{[4
]}

Shi, Junwei ^{[5
]}

Jacobs, Hannah M. ^{[1
]}

Kastritis, Efstathios ^{[1
]}

Gilpatrick, Timothy ^{[1
]}

Paranal, Ronald M. ^{[1
]}

Qi, Jun ^{[1
]}

Chesi, Marta ^{[6
]}

Schinzel, Anna C. ^{[1
]}

McKeown, Michael R. ^{[1
]}

Heffernan, Timothy P. ^{[1
]}

Vakoc, Christopher R. ^{[5
]}

Bergsagel, P. Leif ^{[6
]}

Ghobrial, Irene M. ^{[1
,7
]}

Richardson, Paul G. ^{[1
,7
]}

Young, Richard A. ^{[4
,8
]}

Hahn, William C. ^{[1
,9
]}

Anderson, Kenneth C. ^{[1
,7
]}

Kung, Andrew L. ^{[2
,3
]}

Bradner, James E. ^{[1
,7
]}

Mitsiades, Constantine S. ^{[1
,7
]}

机构：

[1] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA

[2] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA

[3] Childrens Hosp Boston, Boston, MA 02215 USA

[4] Whitehead Inst Biomed Res, Cambridge Ctr 9, Cambridge, MA 02142 USA

[5] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA

[6] Mayo Clin Arizona, Ctr Comprehens Canc, Scottsdale, AZ 85259 USA

[7] Harvard Univ, Dept Med, Sch Med, Boston, MA 02115 USA

[8] MIT, Dept Biol, Cambridge, MA 02142 USA

[9] Broad Inst Harvard & MIT, Cambridge Ctr 7, Cambridge, MA 02142 USA

来源：

CELL | 2011年 / 146卷 / 06期

关键词：

B-CELL LINE; MULTIPLE-MYELOMA; BCL-2; FAMILY; TRANSCRIPTION FACTORS; TRANSGENIC MICE; SOLID TUMORS; BONE-MARROW; EXPRESSION; CANCER; ACTIVATION;

D O I：

10.1016/j.cell.2011.08.017

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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.

引用

页码：903 / 916

页数：14

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