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

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• 作者：Yibin Yang¹ ; ⁷ ; Arthur&#160 ; L. Shaffer III¹ ; ⁷ ; N.C.&#160 ; Tolga Emre¹ ; ⁷ ; ⁸ ; Michele Ceribelli¹ ; Meili Zhang¹ ; George Wright⁴ ; Wenming Xiao² ; John Powell² ; John Platig¹ ; ⁵ ; Holger Kohlhammer¹ ; Ryan&#160 ; M. Young¹ ; Hong Zhao¹ ; Yandan Yang¹ ; Weihong Xu¹ ; Joseph&#160 ; J. Buggy⁶ ; Sriram Balasubramanian⁶ ; Lesley&#160 ; A. Mathews³ ; Paul Shinn³ ; Rajarshi Guha³ ; Marc Ferrer³ ; Craig Thomas³ ; Thomas&#160 ; A. Waldmann¹ ; Louis&#160 ; M. Staudt¹ ; ^{lstaudt@mail.nih.gov}
• 刊名：Cancer Cell
• 出版年：2012
• 期刊代码：43_15356108
• 类别：med
• 出版时间：12 June, 2012
• 卷：21
• 期：6
• 页码：723-737
• 文件大小：1257 K

摘要

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Summary

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 尾 (IFN尾) 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尾 production by repressing IRF7 and amplify prosurvival NF-魏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.