title: B-cell receptor-driven MALT1 activity regulates MYC signaling in mantle cell lymphoma.
abstract: Mantle cell lymphoma (MCL) is a mature B-cell lymphoma characterized by poor clinical outcome. Recent studies revealed the importance of B-cell receptor (BCR) signaling in maintaining MCL survival. However, it remains unclear which role MALT1, an essential component of the CARD11-BCL10-MALT1 complex that links BCR signaling to the NF-κB pathway, plays in the biology of MCL. Here we show that a subset of MCLs is addicted to MALT1, as its inhibition by either RNA or pharmacologic interference induced cytotoxicity both in vitro and in vivo. Gene expression profiling following MALT1 inhibition demonstrated that MALT1 controls an MYC-driven gene expression network predominantly through increasing MYC protein stability. Thus, our analyses identify a previously unappreciated regulatory mechanism of MYC expression. Investigating primary mouse splenocytes, we could demonstrate that MALT1-induced MYC regulation is not restricted to MCL, but represents a common mechanism. MYC itself is pivotal for MCL survival because its downregulation and pharmacologic inhibition induced cytotoxicity in all MCL models. Collectively, these results provide a strong mechanistic rationale to investigate the therapeutic efficacy of targeting the MALT1-MYC axis in MCL patients.
authors.affiliation: Translational Oncology, Albert-Schweitzer-Campus 1, University Hospital Münster, Münster, Germany.|Cluster of Excellence EXC 1003, Cells in Motion, Münster, Germany.|Fachbereich Chemie und Pharmazie, University of Münster, Münster, Germany.
authors.forename: Beiying
authors.initials: B
authors.lastname: Dai
authors.affiliation: Translational Oncology, Albert-Schweitzer-Campus 1, University Hospital Münster, Münster, Germany.|Cluster of Excellence EXC 1003, Cells in Motion, Münster, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Grau
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Juilland
authors.affiliation: Institute of Pathological Physiology, First Faculty of Medicine, Charles University Prague, Prague, Czech Republic.|Department of Hematology, Charles University General Hospital Prague, Prague, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Klener
authors.affiliation: Department of Hematology and Oncology, Robert Bosch Hospital, Stuttgart, Germany.|Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tuebingen, Tuebingen, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Höring
authors.affiliation: Institute of Pathological Physiology, First Faculty of Medicine, Charles University Prague, Prague, Czech Republic.|Department of Hematology, Charles University General Hospital Prague, Prague, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Molinsky
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: Gisela
authors.initials: G
authors.lastname: Schimmack
authors.affiliation: Institute of Human Genetics, Christian-Albrechts University Kiel, Kiel, Germany.
authors.forename: Sietse M
authors.identifier: 0000-0001-5824-0320
authors.initials: SM
authors.lastname: Aukema
authors.affiliation: Department of Internal Medicine III, Ludwig-Maximilians University Hospital Munich, Munich, Germany.|Institute of Medical Informatics, Biometry, and Epidemiology, Ludwig-Maximilians University of Munich, Munich, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Hoster
authors.affiliation: Translational Oncology, Albert-Schweitzer-Campus 1, University Hospital Münster, Münster, Germany.|Hematopathology Section and Lymph Node Registry, Department of Pathology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: Niklas
authors.initials: N
authors.lastname: Vogt
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tuebingen, Tuebingen, Germany.|Department of Clinical Pathology, Robert Bosch Hospital, Stuttgart, Germany.
authors.forename: Annette M
authors.initials: AM
authors.lastname: Staiger
authors.affiliation: Translational Oncology, Albert-Schweitzer-Campus 1, University Hospital Münster, Münster, Germany.|Cluster of Excellence EXC 1003, Cells in Motion, Münster, Germany.
authors.forename: Tabea
authors.initials: T
authors.lastname: Erdmann
authors.affiliation: Translational Oncology, Albert-Schweitzer-Campus 1, University Hospital Münster, Münster, Germany.|Cluster of Excellence EXC 1003, Cells in Motion, Münster, Germany.
authors.forename: Wendan
authors.initials: W
authors.lastname: Xu
authors.affiliation: Translational Oncology, Albert-Schweitzer-Campus 1, University Hospital Münster, Münster, Germany.|Cluster of Excellence EXC 1003, Cells in Motion, Münster, Germany.
authors.forename: Kristian
authors.initials: K
authors.lastname: Erdmann
authors.affiliation: Translational Oncology, Albert-Schweitzer-Campus 1, University Hospital Münster, Münster, Germany.|Cluster of Excellence EXC 1003, Cells in Motion, Münster, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Dzyuba
authors.affiliation: Translational Oncology, Albert-Schweitzer-Campus 1, University Hospital Münster, Münster, Germany.|Cluster of Excellence EXC 1003, Cells in Motion, Münster, Germany.
authors.forename: Hannelore
authors.initials: H
authors.lastname: Madle
authors.affiliation: Cluster of Excellence EXC 1003, Cells in Motion, Münster, Germany.|Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Münster, Münster, Germany.
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Berdel
authors.affiliation: Department of Hematology, Charles University General Hospital Prague, Prague, Czech Republic.
authors.forename: Marek
authors.initials: M
authors.lastname: Trneny
authors.affiliation: Department of Internal Medicine III, Ludwig-Maximilians University Hospital Munich, Munich, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Dreyling
authors.affiliation: Institute of Pathology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Korinna
authors.initials: K
authors.lastname: Jöhrens
authors.affiliation: Department of Physics, Philipps University, Marburg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Lenz
authors.affiliation: Department of Pathology, University of Würzburg, Würzburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Rosenwald
authors.affiliation: Institute of Human Genetics, Christian-Albrechts University Kiel, Kiel, Germany.|Institute of Human Genetics, University Hospital Ulm, Ulm, Germany; and.
authors.forename: Reiner
authors.initials: R
authors.lastname: Siebert
authors.affiliation: Institute of Pathology, University Hospital, Basel, Switzerland.
authors.forename: Alexandar
authors.initials: A
authors.lastname: Tzankov
authors.affiliation: Hematopathology Section and Lymph Node Registry, Department of Pathology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: Wolfram
authors.initials: W
authors.lastname: Klapper
authors.affiliation: Institute of Pathology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Anagnostopoulos
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: Daniel
authors.initials: D
authors.lastname: Krappmann
authors.affiliation: Department of Clinical Pathology, Robert Bosch Hospital, Stuttgart, Germany.
authors.forename: German
authors.initials: G
authors.lastname: Ott
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
authors.forename: Margot
authors.initials: M
authors.lastname: Thome
authors.affiliation: Translational Oncology, Albert-Schweitzer-Campus 1, University Hospital Münster, Münster, Germany.|Cluster of Excellence EXC 1003, Cells in Motion, Münster, Germany.|Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Münster, Münster, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Lenz
mesh_terms: D000818:Animals; D020169:Caspases / Q000378:metabolism* / Q000502:physiology; D016923:Cell Death; D045744:Cell Line, Tumor; D002470:Cell Survival; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000378:metabolism*; D051379:Mice; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism* / Q000502:physiology; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*; D015398:Signal Transduction
chemical_list: C489427:MYC protein, human; D016328:NF-kappa B; D009363:Neoplasm Proteins; D016271:Proto-Oncogene Proteins c-myc; D011947:Receptors, Antigen, B-Cell; D020169:Caspases; C400109:MALT1 protein, human; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein