title: Oncogenic CARMA1 couples NF-κB and β-catenin signaling in diffuse large B-cell lymphomas.
abstract: 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 expressed oncogenic CARMA1 in the NF-κB negative DLBCL lymphoma cell line BJAB. By a proteomic approach we identified recruitment of β-catenin and its destruction complex consisting of APC, AXIN1, CK1α and GSK3β to oncogenic CARMA1. Recruitment of the β-catenin destruction complex was independent of CARMA1-BCL10-MALT1 complex formation or constitutive NF-κB activation and promoted the stabilization of β-catenin. The β-catenin destruction complex was also recruited to CARMA1 in ABC DLBCL cell lines, which coincided with elevated β-catenin expression. In line, β-catenin was frequently detected in non-GCB DLBCL biopsies that rely on chronic BCR signaling. Increased β-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-κB, β-catenin enhanced expression of immunosuppressive interleukin-10 and suppressed antitumoral CCL3, indicating that β-catenin can induce a favorable tumor microenvironment. Thus, parallel activation of NF-κB and β-catenin signaling by gain-of-function mutations in CARMA1 augments WNT stimulation and is required for regulating the expression of distinct NF-κB target genes to trigger cell-intrinsic and extrinsic processes that promote DLBCL lymphomagenesis.
authors.affiliation: Research Unit Cellular Signal Integration, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: M K
authors.initials: MK
authors.lastname: Bognar
authors.affiliation: Research Unit Cellular Signal Integration, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Vincendeau
authors.affiliation: Translational Oncology, Department of Medicine A, Albert-Schweitzer Campus 1, University Hospital Münster, Münster, Germany.|Cluster of Excellence EXC 1003, Cells in Motion, Münster, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Erdmann
authors.affiliation: Research Unit Cellular Signal Integration, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Seeholzer
authors.affiliation: Translational Oncology, Department of Medicine A, Albert-Schweitzer Campus 1, University Hospital Münster, Münster, Germany.|Department of Physics, Philipps-University Marburg, Marburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Grau
authors.affiliation: Institute of Stem Cell Research, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: J R
authors.initials: JR
authors.lastname: Linnemann
authors.affiliation: Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany; German Center for Infection Research (DZIF), partner site Munich, München, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Ruland
authors.affiliation: Institute of Stem Cell Research, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: C H
authors.initials: CH
authors.lastname: Scheel
authors.affiliation: Department of Physics, Philipps-University Marburg, Marburg, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Lenz
authors.affiliation: Department of Clinical Pathology, Robert-Bosch-Krankenhaus, Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Ott
authors.affiliation: Translational Oncology, Department of Medicine A, Albert-Schweitzer Campus 1, University Hospital Münster, Münster, Germany.|Cluster of Excellence EXC 1003, Cells in Motion, Münster, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Lenz
authors.affiliation: Research Unit Protein Science, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: S M
authors.initials: SM
authors.lastname: Hauck
authors.affiliation: Research Unit Cellular Signal Integration, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Krappmann
mesh_terms: D053468:CARD Signaling Adaptor Proteins / Q000235:genetics* / Q000378:metabolism*; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006162:Guanylate Cyclase / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D055550:Protein Stability; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000378:metabolism
chemical_list: D053468:CARD Signaling Adaptor Proteins; D016328:NF-kappa B; D051820:TCF Transcription Factors; D051176:beta Catenin; C417188:RHOJ protein, human; D020741:rho GTP-Binding Proteins; C426242:CARD11 protein, human; D006162:Guanylate Cyclase