IRF4-SPIB
Exploiting Synthetic Lethality for the Therapy of ABC Diffuse Large B Cell Lymphoma
New therapies are needed for the activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), the most refractory subtype of this lymphoma. Oncogenic mutations activate the BCR and MYD88 pathways in ABC DLBCL, engaging NF-?B and IFNß signaling. Lenalidomide, a drug showing clinical activity against DLBCL, kills ABC DLBCLs by inducing IFNß and blocking NF-?B. Lenalidomide antagonizes a central regulatory hub in ABC DLBCL governed by transcription factors IRF4 and SPIB, which together suppress IFNß while augmenting NF-?B. Oncogenic BCR signaling to NF-?B induces IRF4 expression in ABC DLBCL. Inhibition of BCR signaling with the drug ibrutinib synergizes with lenalidomide to block IRF4 and kill ABC DLBCL cells, supporting clinical trials of this synthetically lethal drug combination.
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 ß (IFNß) 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 IFNß 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.