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.

Cluster of Excellence EXC 1003 Cells in Motion Münster Germany

Department of Biochemistry University of Lausanne Epalinges Switzerland

Department of Clinical Pathology Robert Bosch Hospital Stuttgart Germany

Department of Hematology and Oncology Robert Bosch Hospital Stuttgart Germany

Department of Hematology Charles University General Hospital Prague Prague Czech Republic

Department of Internal Medicine 3 Ludwig Maximilians University Hospital Munich Munich Germany

Department of Medicine A Hematology Oncology and Pneumology University Hospital Münster Münster Germany

Department of Pathology University of Würzburg Würzburg Germany

Department of Physics Philipps University Marburg Germany

Dr Margarete Fischer Bosch Institute of Clinical Pharmacology and University of Tuebingen Tuebingen Germany

Fachbereich Chemie und Pharmazie University of Münster Münster Germany

Hematopathology Section and Lymph Node Registry Department of Pathology University Hospital Schleswig Holstein Campus Kiel Kiel Germany

Institute of Human Genetics Christian Albrechts University Kiel Kiel Germany

Institute of Human Genetics University Hospital Ulm Ulm Germany; and

Institute of Medical Informatics Biometry and Epidemiology Ludwig Maximilians University of Munich Munich Germany

Institute of Pathological Physiology 1st Faculty of Medicine Charles University Prague Prague Czech Republic

Institute of Pathology Charité Universitätsmedizin Berlin Berlin Germany

Institute of Pathology University Hospital Basel Switzerland

Research Unit Cellular Signal Integration Institute of Molecular Toxicology and Pharmacology Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany

Translational Oncology Albert Schweitzer Campus 1 University Hospital Münster Münster Germany

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