期刊
ONCOGENE
卷 35, 期 32, 页码 4269-4281出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2015.493
关键词
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资金
- Deutsche Krebshilfe
- Else Krner-Fresenius-Stiftung
- Swiss National Science Foundation (Sinergia grant)
- Deutsche Forschungsgemeinschaft (DFG) [EXC 1003]
- Philipps-University Marburg (Doctoral Scholarship)
- Deutsche Krebshilfe [109434]
Constitutive activation of the antiapoptotic nuclear factor-kappa B (NF-kappa 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-kappa 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-kappa B negative DLBCL lymphoma cell line BJAB. By a proteomic approach we identified recruitment of beta-catenin and its destruction complex consisting of APC, AXIN1, CK1a and GSK3 beta to oncogenic CARMA1. Recruitment of the beta-catenin destruction complex was independent of CARMA1-BCL10-MALT1 complex formation or constitutive NF-kappa B activation and promoted the stabilization of beta-catenin. The beta-catenin destruction complex was also recruited to CARMA1 in ABC DLBCL cell lines, which coincided with elevated beta-catenin expression. In line, beta-catenin was frequently detected in non-GCB DLBCL biopsies that rely on chronic BCR signaling. Increased beta-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-kappa B, beta-catenin enhanced expression of immunosuppressive interleukin-10 and suppressed antitumoral CCL3, indicating that beta-catenin can induce a favorable tumor microenvironment. Thus, parallel activation of NF-kappa B and beta-catenin signaling by gain-of-function mutations in CARMA1 augments WNT stimulation and is required for regulating the expression of distinct NF-kappa B target genes to trigger cell-intrinsic and extrinsic processes that promote DLBCL lymphomagenesis.
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