Activated CARD11 accelerates germinal center kinetics, promoting mTORC1 and terminal differentiation

Abstract

Activating mutations in the adapter protein CARD11 associated with diffuse large B cell lymphomas (DLBCLs) are predicted to arise during germinal center (GC) responses, leading to inappropriate activation of NF-κB signaling. Here, we modeled the B cell-intrinsic impact of the L251P activating mutation in CARD11 (aCARD11) on the GC response. Global B cell aCARD11 expression led to a modest increase in splenic B cells and a severe reduction in B1 B cell numbers, respectively. Following T cell-dependent immunization, aCARD11 cells exhibited increased rates of GC formation, resolution, and differentiation. Restriction of aCARD11 to GC B cells similarly altered the GC response and B cell differentiation. In this model, aCARD11 promoted dark zone skewing along with increased cycling, AID levels, and class switch recombination. Furthermore, aCard11 GC B cells displayed increased biomass and mTORC1 signaling, suggesting a novel strategy for targeting aCARD11-driven DLBCL. While aCARD11 potently impacts GC responses, the rapid GC contraction suggests it requires collaboration with events that limit terminal differentiation to promote lymphoma.

A familial case of B‐cell expansion with NF‐κB and T‐cell anergy caused by a G123D heterozygous missense mutation in the CARD11 gene

“…DLBCL could also be suggestive when considering pharmacological control of B‐cell proliferation. Findings in a transgenic mouse model demonstrated that the inducible expression of a DLBCL‐mimicking CARD11 mutant led to increased mTORC1 signaling in germinal center B cells 19 . In a clinical setting, the mTOR inhibitor sirolimus was administered to two patients with BENTA and relieved their lymphadenopathy and splenomegaly 9 .…”

Nfkbie-deficiency leads to increased susceptibility to develop B-cell lymphoproliferative disorders in aged mice

“…In line with these findings, it was recently shown that activating mutations in CARD11 (observed in~5% of DLBCL (ref. 5 )), a NF-κB activator protein downstream BCR signaling, increases GC formation and GC B-cell proliferation through enhanced cycling 64 . GC B cells represent the origin of several BCLs including DLBCL (ref.…”

Activated interleukin-7 receptor signaling drives B-cell acute lymphoblastic leukemia in mice

“…In vivo EdU labeling for cell cycle analysis was performed as previously described 100 . Briefly, 5-ethynyl-2'-deoxyuridine (EdU, Thermo Fisher) was dissolved in sterile DMSO and 1mg in a volume of 100ul was injected i.p.…”