Exploiting Synthetic Lethality for the Therapy of ABC Diffuse Large B Cell Lymphoma

被引：450

作者：

Yang, Yibin ^{[1
]}

Shaffer, Arthur L., III ^{[1
]}

Emre, N. C. Tolga ^{[1
]}

Ceribelli, Michele ^{[1
]}

Zhang, Meili ^{[1
]}

Wright, George ^{[4
]}

Xiao, Wenming ^{[2
]}

Powell, John ^{[2
]}

Platig, John ^{[1
,5
]}

Kohlhammer, Holger ^{[1
]}

Young, Ryan M. ^{[1
]}

Zhao, Hong ^{[1
]}

Yang, Yandan ^{[1
]}

Xu, Weihong ^{[1
]}

Buggy, Joseph J. ^{[6
]}

Balasubramanian, Sriram ^{[6
]}

Mathews, Lesley A.

Shinn, Paul ^{[3
]}

Guha, Rajarshi ^{[3
]}

Ferrer, Marc ^{[3
]}

Thomas, Craig ^{[3
]}

Waldmann, Thomas A. ^{[1
]}

Staudt, Louis M. ^{[1
]}

机构：

[1] NCI, Metab Branch, Ctr Canc Res, Bethesda, MD 20892 USA

[2] NIH, Bioinformat & Mol Anal Sect, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA

[3] NIH, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA

[4] NCI, Biometr Res Branch, NIH, Rockville, MD 20852 USA

[5] Univ Maryland, Inst Res Elect & Appl Phys, College Pk, MD 20742 USA

[6] Pharmacyclics, Sunnyvale, CA 94085 USA

来源：

CANCER CELL | 2012年 / 21卷 / 06期

关键词：

INTERFERON REGULATORY FACTOR-4; NF-KAPPA-B; MOLECULAR SUBTYPES; POSITIVE FEEDBACK; EXPRESSION; GENE; SURVIVAL; LENALIDOMIDE; INHIBITOR; CHEMOTHERAPY;

D O I：

10.1016/j.ccr.2012.05.024

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Knowledge of oncogenic mutations can inspire therapeutic strategies that are synthetically lethal, affecting cancer cells while sparing normal cells. Lenalidomide is an active agent in the activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), but its mechanism of action is unknown. Lenalidomide kills ABC DLBCL cells by augmenting interferon beta (IFN beta) production, owing to the oncogenic MYD88 mutations in these lymphomas. In a cereblon-dependent fashion, lenalidomide downregulates IRF4 and SPIB, transcription factors that together prevent IFN beta production by repressing IRF7 and amplify prosurvival NF-kappa B signaling by transactivating CARD11. Blockade of B cell receptor signaling using the BTK inhibitor ibrutinib also downregulates IRF4 and consequently synergizes with lenalidomide in killing ABC DLBCLs, suggesting attractive therapeutic strategies.

引用

页码：723 / 737

页数：15

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