Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 42, Pages E4513-E4522Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1406985111
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Funding
- Deutsche Forschungsgemeinschaft [SFB/TRR54, JA1847/1-1, KU1315/7-1, GRK1431]
- Berliner Krebsgesellschaft
- Experimental and Clinical Research Center
- Charite-Universitatsmedizin Berlin
- Max Delbruck Center for Molecular Medicine
- German Cancer Consortium
- Cancer Research UK
- Leukemia Lymphoma Research
- Federation of European Biochemical Societies Long-Term Fellowship
- Polish Ministry of Sciences and Higher Education
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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-kappa B 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.
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