Modeling altered germinal center responses due to oncogenic activating mutations in CARMA1

Abstract

Abstract BCR engagement drives phosphorylation of the multi-adapter, CARMA1, and assembly of signaling complexes required for NF-κB activation. B cell lymphomas are frequently associated with constitutive NF-κB activation that sustains their survival. At least 10% of germinal center (GC) derived, activated B-cell like diffuse large B-cell lymphomas (ABC-DLBCLs) exhibit gain-of-function mutations in CARMA1. In the current study, we directly assess the impact activated CARMA1 (aCARMA1) on GC biology. We developed a novel mouse model that permits inducible expression of aCARMA1. Following T-dependent immunization, mice with B cell intrinsic aCARMA1 exhibit an expanded plasma cell compartment and reduced GC B cell numbers. A similar phenotype was present with GC restricted aCARMA1 expression, leading to increased total and antigen-specific IgG. ABC-DLBCL tumors frequently exhibit somatic mutations predicted to block terminal B cell differentiation. To better define how aCARMA1 impacts GC biology and cooperates with these lesions, we crossed KI mice to Blimp1F/F mice. aCARMA1 expression, in the absence of Blimp1, lead to increased GC B cell numbers compared to controls. Current studies are focused on detailed analysis of this altered response. Our results demonstrate that aCARMA1 is sufficient to alter the GC response and B cell fate, favoring plasma cell development. Further, in the setting of inability to exit the GC, aCARMA1 may be sufficient to directly promote lymphomagenesis.