Oncogenic CARMA1 couples NF-?B and ?-catenin signaling in diffuse large B-cell lymphomas.

Constitutive activation of the antiapoptotic nuclear factor-?B (NF-?B) signaling pathway is a hallmark of the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphomas (DLBCL). Recurrent oncogenic mutations are found in the scaffold protein CARMA1 (CARD11) that connects B-cell receptor (BCR) signaling to the canonical NF-?B pathway. We asked how far additional downstream processes are activated and contribute to the oncogenic potential of DLBCL-derived CARMA1 mutants. To this end, we expressed oncogenic CARMA1 in the NF-?B negative DLBCL lymphoma cell line BJAB. By a proteomic approach we identified recruitment of ?-catenin and its destruction complex consisting of APC, AXIN1, CK1? and GSK3? to oncogenic CARMA1. Recruitment of the ?-catenin destruction complex was independent of CARMA1-BCL10-MALT1 complex formation or constitutive NF-?B activation and promoted the stabilization of ?-catenin. The ?-catenin destruction complex was also recruited to CARMA1 in ABC DLBCL cell lines, which coincided with elevated ?-catenin expression. In line, ?-catenin was frequently detected in non-GCB DLBCL biopsies that rely on chronic BCR signaling. Increased ?-catenin amounts alone were not sufficient to induce classical WNT target gene signatures, but could augment TCF/LEF-dependent transcriptional activation in response to WNT signaling. In conjunction with NF-?B, ?-catenin enhanced expression of immunosuppressive interleukin-10 and suppressed antitumoral CCL3, indicating that ?-catenin can induce a favorable tumor microenvironment. Thus, parallel activation of NF-?B and ?-catenin signaling by gain-of-function mutations in CARMA1 augments WNT stimulation and is required for regulating the expression of distinct NF-?B target genes to trigger cell-intrinsic and extrinsic processes that promote DLBCL lymphomagenesis.     «

Constitutive activation of the antiapoptotic nuclear factor-?B (NF-?B) signaling pathway is a hallmark of the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphomas (DLBCL). Recurrent oncogenic mutations are found in the scaffold protein CARMA1 (CARD11) that connects B-cell receptor (BCR) signaling to the canonical NF-?B pathway. We asked how far additional downstream processes are activated and contribute to the oncogenic potential of DLBCL-derived CARMA1 mutants. To this end, we...     »