Exploiting synthetic lethality for the therapy of ABC diffuse large B cell lymphoma
Yibin Yang, Arthur L Shaffer 3rd, N C Tolga Emre, Michele Ceribelli, Meili Zhang, George Wright, Wenming Xiao, John Powell, John Platig, Holger Kohlhammer, Ryan M Young, Hong Zhao, Yandan Yang, Weihong Xu, Joseph J Buggy, Sriram Balasubramanian, Lesley A Mathews, Paul Shinn, Rajarshi Guha, Marc Ferrer, Craig Thomas, Thomas A Waldmann, Louis M Staudt, Yibin Yang, Arthur L Shaffer 3rd, N C Tolga Emre, Michele Ceribelli, Meili Zhang, George Wright, Wenming Xiao, John Powell, John Platig, Holger Kohlhammer, Ryan M Young, Hong Zhao, Yandan Yang, Weihong Xu, Joseph J Buggy, Sriram Balasubramanian, Lesley A Mathews, Paul Shinn, Rajarshi Guha, Marc Ferrer, Craig Thomas, Thomas A Waldmann, Louis M Staudt
Abstract
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 β (IFNβ) 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 IFNβ production by repressing IRF7 and amplify prosurvival NF-κB 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.
Conflict of interest statement
The other authors declare no competing financial interests.
Copyright © 2012 Elsevier Inc. All rights reserved.
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Source: PubMed