Transcriptional reprogramming by mutated IRF4 in lymphoma
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Published:2023-11-07
Issue:1
Volume:14
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Schleussner NikolaiORCID, Cauchy PierreORCID, Franke VedranORCID, Giefing Maciej, Fornes OriolORCID, Vankadari NaveenORCID, Assi Salam A., Costanza Mariantonia, Weniger Marc A., Akalin AltunaORCID, Anagnostopoulos IoannisORCID, Bukur Thomas, Casarotto Marco G.ORCID, Damm FrederikORCID, Daumke OliverORCID, Edginton-White Benjamin, Gebhardt J. Christof M.ORCID, Grau Michael, Grunwald StephanORCID, Hansmann Martin-Leo, Hartmann SylviaORCID, Huber Lionel, Kärgel Eva, Lusatis Simone, Noerenberg Daniel, Obier Nadine, Pannicke UlrichORCID, Fischer AnjaORCID, Reisser Anja, Rosenwald Andreas, Schwarz KlausORCID, Sundararaj Srinivasan, Weilemann AndreORCID, Winkler Wiebke, Xu Wendan, Lenz GeorgORCID, Rajewsky KlausORCID, Wasserman Wyeth W.ORCID, Cockerill Peter N.ORCID, Scheidereit ClausORCID, Siebert Reiner, Küppers Ralf, Grosschedl RudolfORCID, Janz MartinORCID, Bonifer ConstanzeORCID, Mathas StephanORCID
Abstract
AbstractDisease-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.
Funder
Gouvernement du Canada | Canadian Institutes of Health Research Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada Wilhelm Sander-Stiftung Deutsche Krebshilfe Max-Planck-Gesellschaft Deutsche Forschungsgemeinschaft Kay Kendall Leukaemia Fund
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
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