BCL10 Gain-of-Function Impairs Germinal Center Participation by Naive B Cells and Cooperates with BCL6 to Drive Extrafollicular Diffuse Large B-Cell Lymphoma

BCL10 gain-of-function (GoF) mutations occur in diffuse large B-cell lymphoma (DLBCL) cases of the BN2/C1 molecular subgroup. These alterations activate CARD11-BCL10-MALT1 (CBM) signaling and drive resistance to multiple drug classes, but their role in disease pathogenesis is incompletely understood. In particular, interactions between BCL10 GoF and additional DLBCL oncogenes are undefined. Here, we show BCL10 GoF in naive B cells blocks their participation in germinal center (GC) reactions and permits transformation to DLBCL with a non-GC B-cell phenotype. Most clinical cases with BCL10 GoF also carry translocation of the BCL6 proto-oncogene, and we show that co-activation of these two lesions together promotes pronounced oncogenic synergy. Detailed single-cell analyses of underlying premalignant B-cell populations revealed expansion of extrafollicular memory B cells whose gene-expression program remains prominent in resulting lymphomas in both the mouse and corresponding human tumors. We therefore define a novel role for BCL10 activating mutations in enabling BCL6 lymphomagenesis.