Oncogenic CARMA1 couples NF-B and -Catenin signaling in diffuse large B cell lymphomas

Constitutive activation of the anti-apoptotic NF-B signaling pathway is a hallmark of the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphomas (DLBCL) that is characterized by adverse survival. 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 mutants 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 (CBM) complex formation or constitutive NF-B activation and promoted the stabilization of -Catenin. Elevated -Catenin expression was detected in cell lines and biopsies from ABC DLBCL 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 immune suppressive IL-10 and repressed anti-tumoral CCL3, indicating that -Catenin may induce a favorable tumor microenvironment. Thus, parallel activation of NF-B and -Catenin signaling by gain-of-function mutations in CARMA1 can augment WNT stimulation and is required for maintaining high expression of distinct NF-B target genes and can thereby trigger cell intrinsic and extrinsic processes that promote DLBCL lymphomagenesis.

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Bognar MK, Vincendeau M, Erdmann T, Seeholzer T, Grau M, Linnemann JR, Ruland J, Scheel CH, Lenz P, Ott G, Lenz G, Hauck SM, Krappmann D