title: Inactivation of the putative ubiquitin-E3 ligase PDLIM2 in classical Hodgkin and anaplastic large cell lymphoma.
abstract: Apart from its unique histopathological appearance with rare tumor cells embedded in an inflammatory background of bystander cells, classical Hodgkin lymphoma (cHL) is characterized by an unusual activation of a broad range of signaling pathways involved in cellular activation. This includes constitutive high-level activity of nuclear factor-κB (NF-κB), Janus kinase/signal transducer and activator of transcription (JAK/STAT), activator protein-1 (AP-1) and interferon regulatory factor (IRF) transcription factors (TFs) that are physiologically only transiently activated. Here, we demonstrate that inactivation of the putative ubiquitin E3-ligase PDLIM2 contributes to this TF activation. PDLIM2 expression is lost at the mRNA and protein levels in the majority of cHL cell lines and Hodgkin and Reed-Sternberg (HRS) cells of nearly all cHL primary samples. This loss is associated with PDLIM2 genomic alterations, promoter methylation and altered splicing. Reconstitution of PDLIM2 in HRS cell lines inhibits proliferation, blocks NF-κB transcriptional activity and contributes to cHL-specific gene expression. In non-Hodgkin B-cell lines, small interfering RNA-mediated PDLIM2 knockdown results in superactivation of TFs NF-κB and AP-1 following phorbol 12-myristate 13-acetate (PMA) stimulation. Furthermore, expression of PDLIM2 is lost in anaplastic large cell lymphoma (ALCL) that shares key biological aspects with cHL. We conclude that inactivation of PDLIM2 is a recurrent finding in cHL and ALCL, promotes activation of inflammatory signaling pathways and thereby contributes to their pathogenesis.
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.|Hematology, Oncology, and Tumor Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: K D
authors.initials: KD
authors.lastname: Wurster
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.|Hematology, Oncology, and Tumor Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Hummel
authors.affiliation: Institute of Human Genetics, Christian-Albrechts University Kiel, Kiel, Germany.
authors.forename: J
authors.identifier: 0000-0002-9543-4084
authors.initials: J
authors.lastname: Richter
authors.affiliation: Institute of Human Genetics, Christian-Albrechts University Kiel, Kiel, Germany.|Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
authors.forename: M
authors.initials: M
authors.lastname: Giefing
authors.affiliation: Dr Senckenberg Institute of Pathology, University of Frankfurt, Medical School, Frankfurt, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Hartmann
authors.affiliation: Dr Senckenberg Institute of Pathology, University of Frankfurt, Medical School, Frankfurt, Germany.
authors.forename: M-L
authors.initials: ML
authors.lastname: Hansmann
authors.affiliation: Hematology, Oncology, and Tumor Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Kreher
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.|Hematology, Oncology, and Tumor Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Köchert
authors.affiliation: Research Unit Cellular Signal Integration, Helmholtz Zentrum München für Gesundheit und Umwelt, Neuherberg, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Krappmann
authors.affiliation: Department of Pathology, Haematopathology Section and Lymph Node Registry, Christian-Albrechts University Kiel, Kiel, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Klapper
authors.affiliation: Institute of Pathology, Charité-Universitätsmedzin Berlin, Berlin, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Hummel
authors.affiliation: Hematology, Oncology, and Tumor Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: S-S
authors.initials: SS
authors.lastname: Wenzel
authors.affiliation: Division of Translational Oncology, Department of Medicine A, University Hospital Münster, and Cluster of Excellence EXC 1003, Cells in Motion, Münster, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Lenz
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.|Hematology, Oncology, and Tumor Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Janz
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.|Hematology, Oncology, and Tumor Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany.|German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Dörken
authors.affiliation: Institute of Human Genetics, Christian-Albrechts University Kiel, Kiel, Germany.|Institute of Human Genetics, University Hospital Ulm, Ulm, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Siebert
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.|Hematology, Oncology, and Tumor Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany.|German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Mathas
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D019175:DNA Methylation; D004789:Enzyme Activation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D056426:Genetic Loci; D006689:Hodgkin Disease / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D060588:LIM Domain Proteins / Q000235:genetics* / Q000378:metabolism; D017728:Lymphoma, Large-Cell, Anaplastic / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D059748:Proteolysis; D022821:RNA Splice Sites; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases
chemical_list: D060588:LIM Domain Proteins; D008840:Microfilament Proteins; D016328:NF-kappa B; C502929:PDLIM2 protein, human; D022821:RNA Splice Sites; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases