title: Essential role of IRF4 and MYC signaling for survival of anaplastic large cell lymphoma.
abstract: Anaplastic large cell lymphoma (ALCL) is a distinct entity of T-cell lymphoma that can be divided into 2 subtypes based on the presence of translocations involving the ALK gene (ALK(+) and ALK(-) ALCL). The interferon regulatory factor 4 (IRF4) is known to be highly expressed in both ALK(+) and ALK(-) ALCLs. However, the role of IRF4 in the pathogenesis of these lymphomas remains unclear. Here we show that ALCLs of both subtypes are addicted to IRF4 signaling, as knockdown of IRF4 by RNA interference was toxic to ALCL cell lines in vitro and in ALCL xenograft mouse models in vivo. Gene expression profiling after IRF4 knockdown demonstrated a significant downregulation of a variety of known MYC target genes. Furthermore, our analyses revealed that MYC is a primary target of IRF4, identifying a novel regulatory mechanism of MYC expression and its target gene network in ALCL. MYC, itself, is essential for ALCL survival, as both knockdown of MYC and pharmacologic inhibition of MYC signaling were toxic to ALCL cell lines. Collectively, our results demonstrate that ALCLs are dependent on IRF4 and MYC signaling and that MYC may represent a promising target for future therapies.
authors.affiliation: Department of Medicine A, Translational Oncology, Albert-Schweitzer Campus 1, University Hospital Münster, Münster, Germany; Department of Hematology, Oncology, and Tumor Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany; Cells in Motion Cluster of Excellence, Münster, Germany; Mathematisch-Naturwissenschaftliche Fakultät I, Humboldt University Berlin, Berlin, Germany;
authors.forename: Andre
authors.initials: A
authors.lastname: Weilemann
authors.affiliation: Department of Physics, Philipps-University, Marburg, Germany;
authors.forename: Michael
authors.initials: M
authors.lastname: Grau
authors.affiliation: Department of Medicine A, Translational Oncology, Albert-Schweitzer Campus 1, University Hospital Münster, Münster, Germany; Department of Hematology, Oncology, and Tumor Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany; Cells in Motion Cluster of Excellence, Münster, Germany;
authors.forename: Tabea
authors.initials: T
authors.lastname: Erdmann
authors.affiliation: Department of Experimental Pathology, Medical University Vienna, Wien, Austria;
authors.forename: Olaf
authors.initials: O
authors.lastname: Merkel
authors.affiliation: Department of Molecular Biology and Genetics, Boğaziçi University, Bebek, Istanbul, Turkey;
authors.forename: Ulduz
authors.initials: U
authors.lastname: Sobhiafshar
authors.affiliation: Institute of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany;
authors.forename: Ioannis
authors.initials: I
authors.lastname: Anagnostopoulos
authors.affiliation: Institute of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany;
authors.forename: Michael
authors.initials: M
authors.lastname: Hummel
authors.affiliation: Experimental Pharmacology & Oncology Berlin-Buch GmbH, Berlin, Germany;
authors.forename: Antje
authors.initials: A
authors.lastname: Siegert
authors.affiliation: Department of Hematology, Oncology, and Tumor Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany;
authors.forename: Claudia
authors.initials: C
authors.lastname: Hayford
authors.affiliation: Department of Medicine A, Translational Oncology, Albert-Schweitzer Campus 1, University Hospital Münster, Münster, Germany; Department of Hematology, Oncology, and Tumor Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany; Cells in Motion Cluster of Excellence, Münster, Germany;
authors.forename: Hannelore
authors.initials: H
authors.lastname: Madle
authors.affiliation: Department of Hematology, Oncology, and Tumor Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany; Max-Delbrück-Center for Molecular Medicine, Berlin, Germany;
authors.forename: Brigitte
authors.initials: B
authors.lastname: Wollert-Wulf
authors.affiliation: Experimental Pharmacology & Oncology Berlin-Buch GmbH, Berlin, Germany;
authors.forename: Iduna
authors.initials: I
authors.lastname: Fichtner
authors.affiliation: Department of Hematology, Oncology, and Tumor Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany; Max-Delbrück-Center for Molecular Medicine, Berlin, Germany;
authors.forename: Bernd
authors.initials: B
authors.lastname: Dörken
authors.affiliation: Institute of Pathology, University Hospital, Basel, Switzerland;
authors.forename: Stephan
authors.initials: S
authors.lastname: Dirnhofer
authors.affiliation: Department of Hematology, Oncology, and Tumor Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany; Max-Delbrück-Center for Molecular Medicine, Berlin, Germany;
authors.forename: Stephan
authors.initials: S
authors.lastname: Mathas
authors.affiliation: Department of Hematology, Oncology, and Tumor Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany; Max-Delbrück-Center for Molecular Medicine, Berlin, Germany;
authors.forename: Martin
authors.initials: M
authors.lastname: Janz
authors.affiliation: Department of Molecular Biology and Genetics, Boğaziçi University, Bebek, Istanbul, Turkey;
authors.forename: N C Tolga
authors.initials: NC
authors.lastname: Emre
authors.affiliation: Department of Pathology, University of Würzburg, Würzburg, Germany; and.
authors.forename: Andreas
authors.initials: A
authors.lastname: Rosenwald
authors.affiliation: Department of Clinical Pathology, Robert-Bosch-Krankenhaus, Stuttgart, Germany.
authors.forename: German
authors.initials: G
authors.lastname: Ott
authors.affiliation: Department of Physics, Philipps-University, Marburg, Germany;
authors.forename: Peter
authors.initials: P
authors.lastname: Lenz
authors.affiliation: Institute of Pathology, University Hospital, Basel, Switzerland;
authors.forename: Alexandar
authors.initials: A
authors.lastname: Tzankov
authors.affiliation: Department of Medicine A, Translational Oncology, Albert-Schweitzer Campus 1, University Hospital Münster, Münster, Germany; Department of Hematology, Oncology, and Tumor Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany; Cells in Motion Cluster of Excellence, Münster, Germany;
authors.forename: Georg
authors.initials: G
authors.lastname: Lenz
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D050835:Interferon Regulatory Factors / Q000378:metabolism*; D008223:Lymphoma / Q000378:metabolism; D017728:Lymphoma, Large-Cell, Anaplastic / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D034622:RNA Interference; D012190:Retroviridae / Q000378:metabolism; D015398:Signal Transduction; D000099218:Interferon Regulatory Factor-4
chemical_list: D050835:Interferon Regulatory Factors; D016271:Proto-Oncogene Proteins c-myc; D000099218:Interferon Regulatory Factor-4