Metabolic Signatures Uncover Distinct Targets in Molecular Subsets of Diffuse Large B Cell Lymphoma

被引：431

作者：

Caro, Pilar ^{[1
]}

Kishan, Amar U. ^{[1
,4
]}

Norberg, Erik ^{[1
,5
]}

Stanley, Illana A. ^{[1
,5
]}

Chapuy, Bjoern ^{[2
]}

Ficarro, Scott B. ^{[1
,3
,6
]}

Polak, Klaudia ^{[1
]}

Tondera, Daniel ^{[1
]}

Gounarides, John ^{[7
]}

Yin, Hong ^{[7
]}

Zhou, Feng ^{[1
,3
,6
]}

Green, Michael R. ^{[2
]}

Chen, Linfeng ^{[2
]}

Monti, Stefano ^{[8
,9
]}

Marto, Jarrod A. ^{[1
,3
,6
]}

Shipp, Margaret A. ^{[2
]}

Danial, Nika N. ^{[1
,5
]}

机构：

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

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

[3] Dana Farber Canc Inst, Blais Prote Ctr, Boston, MA 02115 USA

[4] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA

[5] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA

[6] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA

[7] Novartis Inst Biomed Res, Cambridge, MA 02139 USA

[8] Broad Inst, Cambridge, MA 02142 USA

[9] Boston Univ, Sch Med, Sect Computat Biomed, Boston, MA 02218 USA

来源：

CANCER CELL | 2012年 / 22卷 / 04期

基金：

美国国家卫生研究院; 瑞典研究理事会;

关键词：

FATTY-ACID OXIDATION; ACTIVATED RECEPTOR-GAMMA; GLUTAMINE-METABOLISM; CANCER-CELLS; EXPRESSION; PATHWAYS; TUMOR; GROWTH; TISSUE; PROLIFERATION;

D O I：

10.1016/j.ccr.2012.08.014

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Molecular signatures have identified several subsets of diffuse large B cell lymphoma (DLBCL) and rational targets within the B cell receptor (BCR) signaling axis. The OxPhos-DLBCL subset, which harbors the signature of genes involved in mitochondrial metabolism, is insensitive to inhibition of BCR survival signaling but is functionally undefined. We show that, compared with BCR-DLBCLs, OxPhos-DLBCLs display enhanced mitochondrial energy transduction, greater incorporation of nutrient-derived carbons into the tricarboxylic acid cycle, and increased glutathione levels. Moreover, perturbation of the fatty acid oxidation program and glutathione synthesis proved selectively toxic to this tumor subset. Our analysis provides evidence for distinct metabolic fingerprints and associated survival mechanisms in DLBCL and may have therapeutic implications.

引用

页码：547 / 560

页数：14

共 41 条

[1] Advances in the biology and therapy of diffuse large B-cell lymphoma: moving toward a molecularly targeted approach [J].

Abramson, JS ;

Shipp, MA .

BLOOD, 2005, 106 (04) :1164-1174

[2] Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling [J].

Alizadeh, AA ;

Eisen, MB ;

Davis, RE ;

Ma, C ;

Lossos, IS ;

Rosenwald, A ;

Boldrick, JG ;

Sabet, H ;

Tran, T ;

Yu, X ;

Powell, JI ;

Yang, LM ;

Marti, GE ;

Moore, T ;

Hudson, J ;

Lu, LS ;

Lewis, DB ;

Tibshirani, R ;

Sherlock, G ;

Chan, WC ;

Greiner, TC ;

Weisenburger, DD ;

Armitage, JO ;

Warnke, R ;

Levy, R ;

Wilson, W ;

Grever, MR ;

Byrd, JC ;

Botstein, D ;

Brown, PO ;

Staudt, LM .

NATURE, 2000, 403 (6769) :503-511

[3] Balancing biosynthesis and bioenergetics: metabolic programs in oncogenesis [J].

Barger, Jennifer F. ;

Plas, David R. .

[4] SYK-dependent tonic B-cell receptor signaling is a rational treatment target in diffuse large B-cell lymphoma [J].

Chen, Linfeng ;

Monti, Stefano ;

Juszczynski, Przemyslaw ;

Daley, John ;

Chen, Wen ;

Witzig, Thomas E. ;

Habermann, Thomas M. ;

Kutok, Jeffery L. ;

Shipp, Margaret A. .

BLOOD, 2008, 111 (04) :2230-2237

[5] Comprehensive genomic characterization defines human glioblastoma genes and core pathways [J].

Chin, L. ;

Meyerson, M. ;

Aldape, K. ;

Bigner, D. ;

Mikkelsen, T. ;

VandenBerg, S. ;

Kahn, A. ;

Penny, R. ;

Ferguson, M. L. ;

Gerhard, D. S. ;

Getz, G. ;

Brennan, C. ;

Taylor, B. S. ;

Winckler, W. ;

Park, P. ;

Ladanyi, M. ;

Hoadley, K. A. ;

Verhaak, R. G. W. ;

Hayes, D. N. ;

Spellman, Paul T. ;

Absher, D. ;

Weir, B. A. ;

Ding, L. ;

Wheeler, D. ;

Lawrence, M. S. ;

Cibulskis, K. ;

Mardis, E. ;

Zhang, Jinghui ;

Wilson, R. K. ;

Donehower, L. ;

Wheeler, D. A. ;

Purdom, E. ;

Wallis, J. ;

Laird, P. W. ;

Herman, J. G. ;

Schuebel, K. E. ;

Weisenberger, D. J. ;

Baylin, S. B. ;

Schultz, N. ;

Yao, Jun ;

Wiedemeyer, R. ;

Weinstein, J. ;

Sander, C. ;

Gibbs, R. A. ;

Gray, J. ;

Kucherlapati, R. ;

Lander, E. S. ;

Myers, R. M. ;

Perou, C. M. ;

McLendon, Roger .

NATURE, 2008, 455 (7216) :1061-1068

[6] 8-Plex quantitation of changes in cerebrospinal fluid protein expression in subjects undergoing intravenous immunoglobulin treatment for Alzheimer's disease [J].

Choe, Leila ;

D'Ascenzo, Mark ;

Relkin, Norman R. ;

Pappin, Darryl ;

Ross, Philip ;

Williamson, Brian ;

Guertin, Steven ;

Pribil, Patrick ;

Lee, Kelvin H. .

PROTEOMICS, 2007, 7 (20) :3651-3660

[7] Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma [J].

Davis, R. Eric ;

Ngo, Vu N. ;

Lenz, Georg ;

Tolar, Pavel ;

Young, Ryan M. ;

Romesser, Paul B. ;

Kohlhammer, Holger ;

Lamy, Laurence ;

Zhao, Hong ;

Yang, Yandan ;

Xu, Weihong ;

Shaffer, Arthur L. ;

Wright, George ;

Xiao, Wenming ;

Powell, John ;

Jiang, Jian-Kang ;

Thomas, Craig J. ;

Rosenwald, Andreas ;

Ott, German ;

Muller-Hermelink, Hans Konrad ;

Gascoyne, Randy D. ;

Connors, Joseph M. ;

Johnson, Nathalie A. ;

Rimsza, Lisa M. ;

Campo, Elias ;

Jaffe, Elaine S. ;

Wilson, Wyndham H. ;

Delabie, Jan ;

Smeland, Erlend B. ;

Fisher, Richard I. ;

Braziel, Rita M. ;

Tubbs, Raymond R. ;

Cook, J. R. ;

Weisenburger, Dennis D. ;

Chan, Wing C. ;

Pierce, Susan K. ;

Staudt, Louis M. .

NATURE, 2010, 463 (7277) :88-U97

[8] The biology of cancer: Metabolic reprogramming fuels cell growth and proliferation [J].

DeBerardinis, Ralph J. ;

Lum, Julian J. ;

Hatzivassiliou, Georgia ;

Thompson, Craig B. .

CELL METABOLISM, 2008, 7 (01) :11-20

[9] Beyond aerobic glycolysis: Transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis [J].

DeBerardinis, Ralph J. ;

Mancuso, Anthony ;

Daikhin, Evgueni ;

Nissim, Ilana ;

Yudkoff, Marc ;

Wehrli, Suzanne ;

Thompson, Craig B. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2007, 104 (49) :19345-19350

[10] Antigen receptor-mediated changes in glucose metabolism in B lymphocytes: role of phosphatidylinositol 3-kinase signaling in the glycolytic control of growth [J].

Doughty, Cheryl A. ;

Bleiman, Blair F. ;

Wagner, Dean J. ;

Dufort, Fay J. ;

Mataraza, Jennifer M. ;

Roberts, Mary F. ;

Chiles, Thomas C. .

BLOOD, 2006, 107 (11) :4458-4465

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