title: Lymphomagenic CARD11/BCL10/MALT1 signaling drives malignant B-cell proliferation via cooperative NF-κB and JNK activation.
abstract: The aggressive activated B cell-like subtype of diffuse large B-cell lymphoma is characterized by aberrant B-cell receptor (BCR) signaling and constitutive nuclear factor kappa-B (NF-κB) activation, which is required for tumor cell survival. BCR-induced NF-κB activation requires caspase recruitment domain-containing protein 11 (CARD11), and CARD11 gain-of-function mutations are recurrently detected in human diffuse large B-cell lymphoma (DLBCL). To investigate the consequences of dysregulated CARD11 signaling in vivo, we generated mice that conditionally express the human DLBCL-derived CARD11(L225LI) mutant. Surprisingly, CARD11(L225LI) was sufficient to trigger aggressive B-cell lymphoproliferation, leading to early postnatal lethality. CARD11(L225LI) constitutively associated with B-cell CLL/lymphoma 10 (BCL10) and mucosa-associated lymphoid tissue lymphoma translocation gene 1 (MALT1) to simultaneously activate the NF-κB and c-Jun N-terminal kinase (JNK) signaling cascades. Genetic deficiencies of either BCL10 or MALT1 completely rescued the phenotype, and pharmacological inhibition of JNK was, similar to NF-κB blockage, toxic to autonomously proliferating CARD11(L225LI)-expressing B cells. Moreover, constitutive JNK activity was observed in primary human activated B cell-like (ABC)-DLBCL specimens, and human ABC-DLBCL cells were also sensitive to JNK inhibitors. Thus, our results demonstrate that enforced activation of CARD11/BCL10/MALT1 signaling is sufficient to drive transformed B-cell expansion in vivo and identify the JNK pathway as a therapeutic target for ABC-DLBCL.
authors.affiliation: Institut für Klinische Chemie und Pathobiochemie, Klinikum Rechts der Isar, Technische Universität München, 81675 Munich, Germany;
authors.forename: Nathalie
authors.initials: N
authors.lastname: Knies
authors.affiliation: Institut für Klinische Chemie und Pathobiochemie, Klinikum Rechts der Isar, Technische Universität München, 81675 Munich, Germany;
authors.forename: Begüm
authors.initials: B
authors.lastname: Alankus
authors.affiliation: Translational Oncology, Department of Medicine A, University Hospital Münster, 48149 Münster, Germany; Cells in Motion, Cluster of Excellence EXC 1003, 48149 Münster, Germany;
authors.forename: Andre
authors.initials: A
authors.lastname: Weilemann
authors.affiliation: Institute of Pathology, University Hospital Basel, 4031 Basel, Switzerland;
authors.forename: Alexandar
authors.initials: A
authors.lastname: Tzankov
authors.affiliation: Institut für Klinische Chemie und Pathobiochemie, Klinikum Rechts der Isar, Technische Universität München, 81675 Munich, Germany;
authors.forename: Kristina
authors.initials: K
authors.lastname: Brunner
authors.affiliation: Institut für Klinische Chemie und Pathobiochemie, Klinikum Rechts der Isar, Technische Universität München, 81675 Munich, Germany;
authors.forename: Tanja
authors.initials: T
authors.lastname: Ruff
authors.affiliation: Institut für Pathologie, Klinikum Harlaching, 81545 Munich, Germany;
authors.forename: Marcus
authors.initials: M
authors.lastname: Kremer
authors.affiliation: Department of Medicine III, Klinikum Rechts der Isar, Technische Universität München, 81675 Munich, Germany;
authors.forename: Ulrich B
authors.initials: UB
authors.lastname: Keller
authors.affiliation: Translational Oncology, Department of Medicine A, University Hospital Münster, 48149 Münster, Germany; Cells in Motion, Cluster of Excellence EXC 1003, 48149 Münster, Germany;
authors.forename: Georg
authors.initials: G
authors.lastname: Lenz
authors.affiliation: Institut für Klinische Chemie und Pathobiochemie, Klinikum Rechts der Isar, Technische Universität München, 81675 Munich, Germany; German Cancer Consortium, 69120 Heidelberg, Germany; German Center for Infection Research, 81675 München, Germany j.ruland@tum.de.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Ruland
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000074018:B-Cell CLL-Lymphoma 10 Protein; D001402:B-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D015153:Blotting, Western; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism*; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D004789:Enzyme Activation; D005434:Flow Cytometry; D006162:Guanylate Cyclase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; C118591:BCL10 protein, human; D053468:CARD Signaling Adaptor Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D020169:Caspases; C400109:MALT1 protein, human; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; C426242:CARD11 protein, human; D006162:Guanylate Cyclase
keywords: CARD11; JNK; NF-κB; diffuse large B-cell lymphoma; mouse model