Nature Communications (Nov 2023)
Transcriptional reprogramming by mutated IRF4 in lymphoma
- Nikolai Schleussner,
- Pierre Cauchy,
- Vedran Franke,
- Maciej Giefing,
- Oriol Fornes,
- Naveen Vankadari,
- Salam A. Assi,
- Mariantonia Costanza,
- Marc A. Weniger,
- Altuna Akalin,
- Ioannis Anagnostopoulos,
- Thomas Bukur,
- Marco G. Casarotto,
- Frederik Damm,
- Oliver Daumke,
- Benjamin Edginton-White,
- J. Christof M. Gebhardt,
- Michael Grau,
- Stephan Grunwald,
- Martin-Leo Hansmann,
- Sylvia Hartmann,
- Lionel Huber,
- Eva Kärgel,
- Simone Lusatis,
- Daniel Noerenberg,
- Nadine Obier,
- Ulrich Pannicke,
- Anja Fischer,
- Anja Reisser,
- Andreas Rosenwald,
- Klaus Schwarz,
- Srinivasan Sundararaj,
- Andre Weilemann,
- Wiebke Winkler,
- Wendan Xu,
- Georg Lenz,
- Klaus Rajewsky,
- Wyeth W. Wasserman,
- Peter N. Cockerill,
- Claus Scheidereit,
- Reiner Siebert,
- Ralf Küppers,
- Rudolf Grosschedl,
- Martin Janz,
- Constanze Bonifer,
- Stephan Mathas
Affiliations
- Nikolai Schleussner
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Biology of Malignant Lymphomas
- Pierre Cauchy
- Max Planck Institute of Immunobiology and Epigenetics
- Vedran Franke
- Bioinformatics and Omics Data Science Platform, Berlin Institute for Medical Systems Biology, Max-Delbrück-Center
- Maciej Giefing
- Institute of Human Genetics, Polish Academy of Sciences
- Oriol Fornes
- Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, BC Children′s Hospital Research Institute, University of British Columbia
- Naveen Vankadari
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne
- Salam A. Assi
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham
- Mariantonia Costanza
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Biology of Malignant Lymphomas
- Marc A. Weniger
- Institute of Cell Biology (Cancer Research), University of Duisburg-Essen
- Altuna Akalin
- Bioinformatics and Omics Data Science Platform, Berlin Institute for Medical Systems Biology, Max-Delbrück-Center
- Ioannis Anagnostopoulos
- Institute of Pathology, Universität Würzburg and Comprehensive Cancer Centre Mainfranken (CCCMF)
- Thomas Bukur
- TRON gGmbH – Translationale Onkologie an der Universitätsmedizin der Johannes Gutenberg-Universität Mainz
- Marco G. Casarotto
- Research School of Biology, The Australian National University
- Frederik Damm
- Hematology, Oncology, and Cancer Immunology, Charité – Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health
- Oliver Daumke
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Structural Biology
- Benjamin Edginton-White
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham
- J. Christof M. Gebhardt
- Department of Physics, Institute of Biophysics, Ulm University
- Michael Grau
- Department of Physics, University of Marburg
- Stephan Grunwald
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Structural Biology
- Martin-Leo Hansmann
- Frankfurt Institute of Advanced Studies
- Sylvia Hartmann
- Dr. Senckenberg Institute of Pathology, Goethe University Frankfurt
- Lionel Huber
- Max Planck Institute of Immunobiology and Epigenetics
- Eva Kärgel
- Signal Transduction in Tumor Cells, Max-Delbrück-Center for Molecular Medicine
- Simone Lusatis
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Biology of Malignant Lymphomas
- Daniel Noerenberg
- Hematology, Oncology, and Cancer Immunology, Charité – Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health
- Nadine Obier
- Max Planck Institute of Immunobiology and Epigenetics
- Ulrich Pannicke
- Institute for Transfusion Medicine, University of Ulm
- Anja Fischer
- Institute of Human Genetics, Ulm University and Ulm University Medical Center
- Anja Reisser
- Department of Physics, Institute of Biophysics, Ulm University
- Andreas Rosenwald
- Institute of Pathology, Universität Würzburg and Comprehensive Cancer Centre Mainfranken (CCCMF)
- Klaus Schwarz
- Institute for Transfusion Medicine, University of Ulm
- Srinivasan Sundararaj
- Research School of Biology, The Australian National University
- Andre Weilemann
- Medical Department A for Hematology, Oncology and Pneumology, University Hospital Münster
- Wiebke Winkler
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Biology of Malignant Lymphomas
- Wendan Xu
- Medical Department A for Hematology, Oncology and Pneumology, University Hospital Münster
- Georg Lenz
- Medical Department A for Hematology, Oncology and Pneumology, University Hospital Münster
- Klaus Rajewsky
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Immune Regulation and Cancer
- Wyeth W. Wasserman
- Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, BC Children′s Hospital Research Institute, University of British Columbia
- Peter N. Cockerill
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham
- Claus Scheidereit
- Signal Transduction in Tumor Cells, Max-Delbrück-Center for Molecular Medicine
- Reiner Siebert
- Institute of Human Genetics, Christian-Albrechts-University Kiel
- Ralf Küppers
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
- Rudolf Grosschedl
- Max Planck Institute of Immunobiology and Epigenetics
- Martin Janz
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Biology of Malignant Lymphomas
- Constanze Bonifer
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham
- Stephan Mathas
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Biology of Malignant Lymphomas
- DOI
- https://doi.org/10.1038/s41467-023-41954-8
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 1 – 18
Abstract
Abstract Disease-causing mutations in genes encoding transcription factors (TFs) can affect TF interactions with their cognate DNA-binding motifs. Whether and how TF mutations impact upon the binding to TF composite elements (CE) and the interaction with other TFs is unclear. Here, we report a distinct mechanism of TF alteration in human lymphomas with perturbed B cell identity, in particular classic Hodgkin lymphoma. It is caused by a recurrent somatic missense mutation c.295 T > C (p.Cys99Arg; p.C99R) targeting the center of the DNA-binding domain of Interferon Regulatory Factor 4 (IRF4), a key TF in immune cells. IRF4-C99R fundamentally alters IRF4 DNA-binding, with loss-of-binding to canonical IRF motifs and neomorphic gain-of-binding to canonical and non-canonical IRF CEs. IRF4-C99R thoroughly modifies IRF4 function by blocking IRF4-dependent plasma cell induction, and up-regulates disease-specific genes in a non-canonical Activator Protein-1 (AP-1)-IRF-CE (AICE)-dependent manner. Our data explain how a single mutation causes a complex switch of TF specificity and gene regulation and open the perspective to specifically block the neomorphic DNA-binding activities of a mutant TF.
