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

Stephan Kreher, M Amine Bouhlel, Pierre Cauchy, 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 RajewskyGeorg Lenz, Peter N Cockerill, Martin Janz, Bernd Dörken, Constanze Bonifer, Stephan Mathas

Research output: Contribution to journalArticlepeer-review

39 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)E4513–E4522
JournalNational Academy of Sciences. Proceedings
Volume111
Issue number42
Early online date6 Oct 2014
DOIs
Publication statusPublished - 21 Oct 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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