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

ABSTRACT: 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.

SUBMITTER: Bognar MK

PROVIDER: S-EPMC4981874 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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

Bognar M K MK Vincendeau M M Erdmann T T Seeholzer T T Grau M M Linnemann J R JR Ruland J J Scheel C H CH Lenz P P Ott G G Lenz G G Hauck S M SM Krappmann D D

Oncogene 20160118 32

Constitutive activation of the antiapoptotic nuclear factor-κB (NF-κB) 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-κB 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 ...[more]

PMID: 26776161

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Project description:Constitutive activation of the anti-apoptotic NF-ÎºB 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-ÎºB 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-ÎºB negative DLBCL lymphoma cell line BJAB. By a proteomic approach we identified recruitment of Î²-Catenin and its destruction complex consisting of APC, AXIN1, CK1Î± and GSK3Î² to oncogenic CARMA1. Recruitment of the Î²-Catenin destruction complex was independent of CARMA1-BCL10-MALT1 (CBM) complex formation or constitutive NF-ÎºB activation and promoted the stabilization of Î²-Catenin. Elevated Î²-Catenin expression was detected in cell lines and biopsies from ABC DLBCL that rely on chronic BCR signaling. Increased Î²-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-ÎºB, Î²-Catenin enhanced expression of immune suppressive IL-10 and repressed anti-tumoral CCL3, indicating that Î²-Catenin may induce a favorable tumor microenvironment. Thus, parallel activation of NF-ÎºB and Î²-Catenin signaling by gain-of-function mutations in CARMA1 can augment WNT stimulation and is required for maintaining high expression of distinct NF-ÎºB target genes and can thereby trigger cell intrinsic and extrinsic processes that promote DLBCL lymphomagenesis. CARMA1 mutants were expressed in BJAB, an NF-ÎºB negative GCB DLBCL lymphoma cell line. Gene expression induced by GCB DLBCL derived CARMA1 L225LI mutant was compared with the empty vector (mock) control, CARMA1 WT, CARMA1 point mutant R35A and with CARMA1 double mutant R35A/L225LI.

Dataset Information

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

Publications

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

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