Mapping of transcription factor motifs in active chromatin identifies IRF5 as key regulator in classical Hodgkin lymphoma

Research output: Contribution to journalArticlepeer-review

Authors

  • Stephan Kreher
  • M Amine Bouhlel
  • Björn Lamprecht
  • Shuang Li
  • Michael Grau
  • Franziska Hummel
  • Karl Köchert
  • Ioannis Anagnostopoulos
  • Korinna Jöhrens
  • Michael Hummel
  • John Hiscott
  • Sören-Sebastian Wenzel
  • Peter Lenz
  • Markus Schneider
  • Ralf Küppers
  • Claus Scheidereit
  • Maciej Giefing
  • Reiner Siebert
  • Klaus Rajewsky
  • Georg Lenz
  • Martin Janz
  • Bernd Dörken
  • Stephan Mathas

External organisations

  • Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany; Hematology, Oncology, and Tumor Immunology, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany;
  • University of Leeds
  • 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;
  • Department of Physics, Philipps University, 35052 Marburg, Germany;
  • Institute of Pathology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany;
  • German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Institute of Pathology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany;
  • Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, FL 34987;
  • Hematology, Oncology, and Tumor Immunology, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany;
  • Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, 45122 Essen, Germany;
  • Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany;
  • 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.
  • Institute of Human Genetics, Christian-Albrechts University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany; and.
  • 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.

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.

Details

Original languageEnglish
Pages (from-to)E4513–E4522
JournalNational Academy of Sciences. Proceedings
Volume111
Issue number42
Publication statusPublished - 21 Oct 2014