Discovery and Characterization of Super-Enhancer-Associated Dependencies in Diffuse Large B Cell Lymphoma

被引：613

作者：

Chapuy, Bjoern ^{[1
]}

McKeown, Michael R. ^{[1
]}

Lin, Charles Y. ^{[1
]}

Monti, Stefano ^{[2
]}

Roemer, Margaretha G. M. ^{[1
]}

Qi, Jun ^{[1
]}

Rahl, Peter B. ^{[3
]}

Sun, Heather H. ^{[4
]}

Yeda, Kelly T. ^{[1
]}

Doench, John G. ^{[5
]}

Reichert, Elaine ^{[1
]}

Kung, Andrew L. ^{[6
]}

Rodig, Scott J. ^{[4
]}

Young, Richard A. ^{[3
]}

Shipp, Margaret A. ^{[1
]}

Bradner, James E. ^{[1
]}

机构：

[1] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[2] Boston Univ, Sch Med, Sect Computat Biomed, Boston, MA 02118 USA

[3] MIT, Whitehead Inst Genome Res, Cambridge, MA 02142 USA

[4] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

[5] Broad Inst, Cambridge, MA 02142 USA

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

来源：

CANCER CELL | 2013年 / 24卷 / 06期

基金：

美国国家卫生研究院;

关键词：

BET BROMODOMAIN INHIBITION; OCA-B; SELECTIVE-INHIBITION; GENE-EXPRESSION; P-TEFB; C-MYC; TRANSCRIPTION; LEUKEMIA; BRD4; CHROMATIN;

D O I：

10.1016/j.ccr.2013.11.003

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Diffuse large B cell lymphoma (DLBCL) is a biologically heterogeneous and clinically aggressive disease. Here, we explore the role of bromodomain and extra-terminal domain (BET) proteins in DLBCL, using integrative chemical genetics and functional epigenomics. We observe highly asymmetric loading of bromodomain 4 (BRD4) at enhancers, with approximately 33% of all BRD4 localizing to enhancers at 1.6% of occupied genes. These super-enhancers prove particularly sensitive to bromodomain inhibition, explaining the selective effect of BET inhibitors on oncogenic and lineage-specific transcriptional circuits. Functional study of genes marked by super-enhancers identifies DLBCLs dependent on OCA-B and suggests a strategy for discovering unrecognized cancer dependencies. Translational studies performed on a comprehensive panel of DLBCLs establish a therapeutic rationale for evaluating BET inhibitors in this disease.

引用

页码：777 / 790

页数：14

共 51 条

[1] Bromodomain and Extra-terminal (BET) Bromodomain Inhibition Activate Transcription via Transient Release of Positive Transcription Elongation Factor b (P-TEFb) from 7SK Small Nuclear Ribonucleoprotein [J].

Bartholomeeusen, Koen ;

Xiang, Yanhui ;

Fujinaga, Koh ;

Peterlin, B. Matija .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2012, 287 (43) :36609-36616

[2] Roles of BCL6 in normal and transformed germinal center B cells [J].

Basso, Katia ;

Dalla-Favera, Riccardo .

IMMUNOLOGICAL REVIEWS, 2012, 247 :172-183

[3] Conserved P-TEFb-interacting domain of BRD4 inhibits HIV transcription [J].

Bisgrovet, Dwayne A. ;

Mahmoudi, Tokameh ;

Henklein, Peter ;

Verdin, Eric .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2007, 104 (34) :13690-13695

[4] Metabolic Signatures Uncover Distinct Targets in Molecular Subsets of Diffuse Large B Cell Lymphoma [J].

Caro, Pilar ;

Kishan, Amar U. ;

Norberg, Erik ;

Stanley, Illana A. ;

Chapuy, Bjoern ;

Ficarro, Scott B. ;

Polak, Klaudia ;

Tondera, Daniel ;

Gounarides, John ;

Yin, Hong ;

Zhou, Feng ;

Green, Michael R. ;

Chen, Linfeng ;

Monti, Stefano ;

Marto, Jarrod A. ;

Shipp, Margaret A. ;

Danial, Nika N. .

CANCER CELL, 2012, 22 (04) :547-560

[5] Introduction [J].

Chen, Ling .

MANAGEMENT COMMUNICATION QUARTERLY, 2013, 27 (01) :3-5

[6] Pax5: the guardian of B cell identity and function [J].

Cobaleda, Cesar ;

Schebesta, Alexandra ;

Delogu, Alessio ;

Busslinger, Meinrad .

NATURE IMMUNOLOGY, 2007, 8 (05) :463-470

[7] Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia [J].

Dawson, Mark A. ;

Prinjha, Rab K. ;

Dittmann, Antje ;

Giotopoulos, George ;

Bantscheff, Marcus ;

Chan, Wai-In ;

Robson, Samuel C. ;

Chung, Chun-wa ;

Hopf, Carsten ;

Savitski, Mikhail M. ;

Huthmacher, Carola ;

Gudgin, Emma ;

Lugo, Dave ;

Beinke, Soren ;

Chapman, Trevor D. ;

Roberts, Emma J. ;

Soden, Peter E. ;

Auger, Kurt R. ;

Mirguet, Olivier ;

Doehner, Konstanze ;

Delwel, Ruud ;

Burnett, Alan K. ;

Jeffrey, Phillip ;

Drewes, Gerard ;

Lee, Kevin ;

Huntly, Brian J. P. ;

Kouzarides, Tony .

NATURE, 2011, 478 (7370) :529-533

[8] BET Bromodomain Inhibition as a Therapeutic Strategy to Target c-Myc [J].

Delmore, Jake E. ;

Issa, Ghayas C. ;

Lemieux, Madeleine E. ;

Rahl, Peter B. ;

Shi, Junwei ;

Jacobs, Hannah M. ;

Kastritis, Efstathios ;

Gilpatrick, Timothy ;

Paranal, Ronald M. ;

Qi, Jun ;

Chesi, Marta ;

Schinzel, Anna C. ;

McKeown, Michael R. ;

Heffernan, Timothy P. ;

Vakoc, Christopher R. ;

Bergsagel, P. Leif ;

Ghobrial, Irene M. ;

Richardson, Paul G. ;

Young, Richard A. ;

Hahn, William C. ;

Anderson, Kenneth C. ;

Kung, Andrew L. ;

Bradner, James E. ;

Mitsiades, Constantine S. .

CELL, 2011, 146 (06) :903-916

[9] Histone Recognition and Large-Scale Structural Analysis of the Human Bromodomain Family [J].

Filippakopoulos, Panagis ;

Picaud, Sarah ;

Mangos, Maria ;

Keates, Tracy ;

Lambert, Jean-Philippe ;

Barsyte-Lovejoy, Dalia ;

Felletar, Ildiko ;

Volkmer, Rudolf ;

Mueller, Susanne ;

Pawson, Tony ;

Gingras, Anne-Claude ;

Arrowsmith, Cheryl H. ;

Knapp, Stefan .

CELL, 2012, 149 (01) :214-231

[10] Selective inhibition of BET bromodomains [J].

Filippakopoulos, Panagis ;

Qi, Jun ;

Picaud, Sarah ;

Shen, Yao ;

Smith, William B. ;

Fedorov, Oleg ;

Morse, Elizabeth M. ;

Keates, Tracey ;

Hickman, Tyler T. ;

Felletar, Ildiko ;

Philpott, Martin ;

Munro, Shonagh ;

McKeown, Michael R. ;

Wang, Yuchuan ;

Christie, Amanda L. ;

West, Nathan ;

Cameron, Michael J. ;

Schwartz, Brian ;

Heightman, Tom D. ;

La Thangue, Nicholas ;

French, Christopher A. ;

Wiest, Olaf ;

Kung, Andrew L. ;

Knapp, Stefan ;

Bradner, James E. .

NATURE, 2010, 468 (7327) :1067-1073

← 1 2 3 4 5 6 →