Exploiting synthetic lethality for the therapy of ABC diffuse large B cell lymphoma.

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Exploiting synthetic lethality for the therapy of ABC diffuse large B cell lymphoma.

Cancer Cell. 2012 Jun 12;21(6):723-37

Authors: Yang Y, Shaffer AL, Emre NC, Ceribelli M, Zhang M, Wright G, Xiao W, Powell J, Platig J, Kohlhammer H, Young RM, Zhao H, Yang Y, Xu W, Buggy JJ, Balasubramanian S, Mathews LA, Shinn P, Guha R, Ferrer M, Thomas C, Waldmann TA, Staudt LM

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

PMID: 22698399 [PubMed - indexed for MEDLINE]

NF-kB signaling pathway