Exploiting Synthetic Lethality for the Therapy of ABC Diffuse Large B Cell Lymphoma
Menée in vitro et à l'aide de xénogreffes, cette étude suggère que la combinaison du lénalidomide et de l'ibrutinib, un inhibiteur de BTK, mettrait en oeuvre un mécanisme de létalité synthétique efficace pour le traitement du sous-type ABC des lymphomes diffus à grandes cellules B
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 ² (IFN²) 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 IFN² production by repressing IRF7 and amplify prosurvival NF-ºB 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. º Lenalidomide kills ABC DLBCLs by decreasing expression of IRF4 and SPIB º IRF4 and SPIB maintain ABC DLBCL viability º IRF4 and SPIB block toxic IFN² production while enhancing prosurvival NF-ºB activity º Lenalidomide and BCR pathway drugs synergize to inhibit IRF4 and kill ABC DLBCLs