Author/Authors :
Yang، نويسنده , , Yibin and Shaffer III، نويسنده , , Arthur L. and Emre، نويسنده , , N.C. Tolga and Ceribelli، نويسنده , , Michele and Zhang، نويسنده , , Meili and Wright، نويسنده , , George and Xiao، نويسنده , , Wenming and Powell، نويسنده , , John and Platig، نويسنده , , John and Kohlhammer، نويسنده , , Holger and Young، نويسنده , , Ryan M. and Zhao، نويسنده , , Hong and Yang، نويسنده , , Yandan and Xu، نويسنده , , Weihong and Buggy، نويسنده , , Joseph J. and Balasubramanian، نويسنده , , Sriram and Mathews، نويسنده , , Lesley A. and Shinn، نويسنده , , Paul and Guha، نويسنده , , Rajarshi and Ferrer، نويسنده , , Marc and Thomas، نويسنده , , Craig and Waldmann، نويسنده , , Thomas A. and Staudt، نويسنده , , Louis M.، نويسنده ,
Abstract :
Summary
dge 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.
