Lymphomagenic CARD11/BCL10/MALT1 signaling drives malignant B-cell proliferation via cooperative NF-κB and JNK activation

Abstract

The aggressive activated B cell-like subtype of diffuse large B-cell lymphoma is characterized by aberrant B-cell receptor (BCR) signaling and constitutive nuclear factor kappa-B (NF-κB) activation, which is required for tumor cell survival. BCR-induced NF-κB activation requires caspase recruitment domain-containing protein 11 (CARD11), and CARD11 gain-of-function mutations are recurrently detected in human diffuse large B-cell lymphoma (DLBCL). To investigate the consequences of dysregulated CARD11 signaling in vivo, we generated mice that conditionally express the human DLBCL-derived CARD11(L225LI) mutant. Surprisingly, CARD11(L225LI) was sufficient to trigger aggressive B-cell lymphoproliferation, leading to early postnatal lethality. CARD11(L225LI) constitutively associated with B-cell CLL/lymphoma 10 (BCL10) and mucosa-associated lymphoid tissue lymphoma translocation gene 1 (MALT1) to simultaneously activate the NF-κB and c-Jun N-terminal kinase (JNK) signaling cascades. Genetic deficiencies of either BCL10 or MALT1 completely rescued the phenotype, and pharmacological inhibition of JNK was, similar to NF-κB blockage, toxic to autonomously proliferating CARD11(L225LI)-expressing B cells. Moreover, constitutive JNK activity was observed in primary human activated B cell-like (ABC)-DLBCL specimens, and human ABC-DLBCL cells were also sensitive to JNK inhibitors. Thus, our results demonstrate that enforced activation of CARD11/BCL10/MALT1 signaling is sufficient to drive transformed B-cell expansion in vivo and identify the JNK pathway as a therapeutic target for ABC-DLBCL.

Lymphocyte signaling and activation by the CARMA1-BCL10-MALT1 signalosome

“…Further, expression of oncogenic CARMA1 in murine B cells induces lymphocyte proliferation and post-natal lethality (Knies et al, 2015). As discussed earlier (see section 'Physiological role of the CBM complex in lymphocytes'), activating CARMA1 germline mutations induce the BENTA phenotype in humans that is characterized by B cell expansion, but at the same time T cell hyporesponsiveness and anergy (Snow et al, 2012).…”

Pathophysiological significance and therapeutic targeting of germinal center kinase in diffuse large B-cell lymphoma

“…Consequently, the residual low levels of p-JNK observed after treatment with HG6-64-1 may lead to a better therapeutic window compared with direct JNK inhibitors. However, Jun-regulated genes activation was recently reported to promote lymphoma growth and dissemination to extranodal sites in DLBCL, 41 and the JNK pathway was reported as a therapeutic target in ABC-like DLBCL 42 ; so it is possible that direct JNK inhibition should be revisited in future studies.…”

The innate immune signaling in cancer and cardiometabolic diseases: Friends or foes?

“…In colon cancer, CARD9 enhances liver metastasis by promoting metastasis-associated macrophage polarization through NF-κB signaling [145]. Bcl-10/Malt1 also activates NF-κB and JNK signaling, thus promoting the proliferation of malignant B-cells [146]. Therefore, Malt1 inhibition specifically suppresses activated B cell-like-diffuse large B cell lymphoma [147].…”