Recurrent mutations, including NPM1c, activate a BRD4-dependent core transcriptional program in acute myeloid leukemia

被引：150

作者：

Dawson, M. A. ^{[1
,2
,3
,4
,5
]}

Gudgin, E. J. ^{[1
,2
]}

Horton, S. J. ^{[1
,2
,3
]}

Giotopoulos, G. ^{[1
,2
,3
]}

Meduri, E. ^{[1
,2
,3
]}

Robson, S. ^{[4
,5
]}

Cannizzaro, E. ^{[1
,2
,4
,5
]}

Osaki, H. ^{[1
,2
,3
]}

Wiese, M. ^{[1
,2
,4
,5
]}

Putwain, S. ^{[1
,2
,3
]}

Fong, C. Y. ^{[1
,2
,4
,5
]}

Grove, C. ^{[6
]}

Craig, J. ^{[1
,2
]}

Dittmann, A. ^{[7
]}

Lugo, D. ^{[8
]}

Jeffrey, P. ^{[8
]}

Drewes, G. ^{[7
]}

Lee, K. ^{[8
]}

Bullinger, L. ^{[9
]}

Prinjha, R. K.

Kouzarides, T. ^{[4
,5
]}

Vassiliou, G. S. ^{[1
,2
,6
]}

Huntly, B. J. P. ^{[1
,2
,3
]}

机构：

[1] Univ Cambridge, Cambridge Inst Med Res, Dept Haematol, Cambridge CB2 0XY, England

[2] Univ Cambridge, Addenbrookes Hosp, Cambridge CB2 0XY, England

[3] Wellcome Trust Med Res Council, Cambridge Stem Cell Inst, Cambridge, England

[4] Univ Cambridge, Gurdon Inst, Cambridge CB2 0XY, England

[5] Univ Cambridge, Dept Pathol, Cambridge CB2 0XY, England

[6] Wellcome Trust Sanger Inst, Haematol Canc Genet, Hinxton, England

[7] Cellzome AG, Discovery Res, Heidelberg, Germany

[8] GlaxoSmithKline, Med Res Ctr, Immunoinflammat Ctr Excellence Drug Discovery, Epinova DPU, Stevenage, Herts, England

[9] Univ Hosp Ulm, Dept Internal Med 3, Ulm, Germany

来源：

LEUKEMIA | 2014年 / 28卷 / 02期

基金：

英国惠康基金;

关键词：

acute myeloid leukemia; epigenetic therapy; BET protein; nucleophosmin mutation; biomarker; GENE-EXPRESSION PROFILE; CYTOPLASMIC NUCLEOPHOSMIN; MUTANT NUCLEOPHOSMIN; INHIBITION; TARGET;

D O I：

10.1038/leu.2013.338

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Recent evidence suggests that inhibition of bromodomain and extra-terminal (BET) epigenetic readers may have clinical utility against acute myeloid leukemia (AML). Here we validate this hypothesis, demonstrating the efficacy of the BET inhibitor I-BET151 across a variety of AML subtypes driven by disparate mutations. We demonstrate that a common 'core' transcriptional program, which is HOX gene independent, is downregulated in AML and underlies sensitivity to I-BET treatment. This program is enriched for genes that contain 'super-enhancers', recently described regulatory elements postulated to control key oncogenic driver genes. Moreover, our program can independently classify AML patients into distinct cytogenetic and molecular subgroups, suggesting that it contains biomarkers of sensitivity and response. We focus AML with mutations of the Nucleophosmin gene (NPM1) and show evidence to suggest that wild-type NPM1 has an inhibitory influence on BRD4 that is relieved upon NPM1c mutation and cytosplasmic dislocation. This leads to the upregulation of the core transcriptional program facilitating leukemia development. This program is abrogated by I-BET therapy and by nuclear restoration of NPM1. Finally, we demonstrate the efficacy of I-BET151 in a unique murine model and in primary patient samples of NPM1c AML. Taken together, our data support the use of BET inhibitors in clinical trials in AML.

引用

页码：311 / 320

页数：10

共 31 条

[31] RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia [J].

Zuber, Johannes ;

Shi, Junwei ;

Wang, Eric ;

Rappaport, Amy R. ;

Herrmann, Harald ;

Sison, Edward A. ;

Magoon, Daniel ;

Qi, Jun ;

Blatt, Katharina ;

Wunderlich, Mark ;

Taylor, Meredith J. ;

Johns, Christopher ;

Chicas, Agustin ;

Mulloy, James C. ;

Kogan, Scott C. ;

Brown, Patrick ;

Valent, Peter ;

Bradner, James E. ;

Lowe, Scott W. ;

Vakoc, Christopher R. .

NATURE, 2011, 478 (7370) :524-U124

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