title: Mapping of transcription factor motifs in active chromatin identifies IRF5 as key regulator in classical Hodgkin lymphoma.
abstract: Deregulated transcription factor (TF) activities are commonly observed in hematopoietic malignancies. Understanding tumorigenesis therefore requires determining the function and hierarchical role of individual TFs. To identify TFs central to lymphomagenesis, we identified lymphoma type-specific accessible chromatin by global mapping of DNaseI hypersensitive sites and analyzed enriched TF-binding motifs in these regions. Applying this unbiased approach to classical Hodgkin lymphoma (HL), a common B-cell-derived lymphoma with a complex pattern of deregulated TFs, we discovered interferon regulatory factor (IRF) sites among the top enriched motifs. High-level expression of the proinflammatory TF IRF5 was specific to HL cells and crucial for their survival. Furthermore, IRF5 initiated a regulatory cascade in human non-Hodgkin B-cell lines and primary murine B cells by inducing the TF AP-1 and cooperating with NF-κB to activate essential characteristic features of HL. Our strategy efficiently identified a lymphoma type-specific key regulator and uncovered a tumor promoting role of IRF5.
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany; Hematology, Oncology, and Tumor Immunology, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany;
authors.forename: Stephan
authors.initials: S
authors.lastname: Kreher
authors.affiliation: Leeds Institute of Molecular Medicine, University of Leeds, Leeds LS9 7TF, United Kingdom;
authors.forename: M Amine
authors.initials: MA
authors.lastname: Bouhlel
authors.affiliation: School of Cancer Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom;
authors.forename: Pierre
authors.initials: P
authors.lastname: Cauchy
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany; Hematology, Oncology, and Tumor Immunology, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany;
authors.forename: Björn
authors.initials: B
authors.lastname: Lamprecht
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany; Hematology, Oncology, and Tumor Immunology, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany;
authors.forename: Shuang
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Physics, Philipps University, 35052 Marburg, Germany;
authors.forename: Michael
authors.initials: M
authors.lastname: Grau
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany; Hematology, Oncology, and Tumor Immunology, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany;
authors.forename: Franziska
authors.initials: F
authors.lastname: Hummel
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany; Hematology, Oncology, and Tumor Immunology, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany;
authors.forename: Karl
authors.initials: K
authors.lastname: Köchert
authors.affiliation: Institute of Pathology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany;
authors.forename: Ioannis
authors.initials: I
authors.lastname: Anagnostopoulos
authors.affiliation: Institute of Pathology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany;
authors.forename: Korinna
authors.initials: K
authors.lastname: Jöhrens
authors.affiliation: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Institute of Pathology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany;
authors.forename: Michael
authors.initials: M
authors.lastname: Hummel
authors.affiliation: Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, FL 34987;
authors.forename: John
authors.initials: J
authors.lastname: Hiscott
authors.affiliation: Hematology, Oncology, and Tumor Immunology, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany;
authors.forename: Sören-Sebastian
authors.initials: SS
authors.lastname: Wenzel
authors.affiliation: Department of Physics, Philipps University, 35052 Marburg, Germany;
authors.forename: Peter
authors.initials: P
authors.lastname: Lenz
authors.affiliation: Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, 45122 Essen, Germany;
authors.forename: Markus
authors.initials: M
authors.lastname: Schneider
authors.affiliation: Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, 45122 Essen, Germany;
authors.forename: Ralf
authors.initials: R
authors.lastname: Küppers
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany;
authors.forename: Claus
authors.initials: C
authors.lastname: Scheidereit
authors.affiliation: Institute of Human Genetics, Christian-Albrechts University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany; and Institute of Human Genetics, Polish Academy of Sciences, 60-479 Poznan, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Giefing
authors.affiliation: Institute of Human Genetics, Christian-Albrechts University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany; and.
authors.forename: Reiner
authors.initials: R
authors.lastname: Siebert
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany;
authors.forename: Klaus
authors.initials: K
authors.lastname: Rajewsky
authors.affiliation: Hematology, Oncology, and Tumor Immunology, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany;
authors.forename: Georg
authors.initials: G
authors.lastname: Lenz
authors.affiliation: School of Cancer Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom;
authors.forename: Peter N
authors.initials: PN
authors.lastname: Cockerill
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany; Hematology, Oncology, and Tumor Immunology, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany;
authors.forename: Martin
authors.initials: M
authors.lastname: Janz
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany; Hematology, Oncology, and Tumor Immunology, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany;
authors.forename: Bernd
authors.initials: B
authors.lastname: Dörken
authors.affiliation: School of Cancer Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom; c.bonifer@bham.ac.uk stephan.mathas@charite.de.
authors.forename: Constanze
authors.initials: C
authors.lastname: Bonifer
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany; Hematology, Oncology, and Tumor Immunology, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; c.bonifer@bham.ac.uk stephan.mathas@charite.de.
authors.forename: Stephan
authors.initials: S
authors.lastname: Mathas
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology; D045744:Cell Line, Tumor; D019070:Cell Lineage; D018925:Chemokines / Q000378:metabolism; D002633:Chemotaxis; D002843:Chromatin / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D003850:Deoxyribonuclease I / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006689:Hodgkin Disease / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007249:Inflammation; D050835:Interferon Regulatory Factors / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008223:Lymphoma / Q000378:metabolism; D008228:Lymphoma, Non-Hodgkin / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010957:Plasmids / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D018808:Transcription Factor AP-1 / Q000378:metabolism*
chemical_list: D018925:Chemokines; D002843:Chromatin; D016207:Cytokines; C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D003850:Deoxyribonuclease I