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Schleussner, Nikolai; Cauchy, Pierre; Franke, Vedran; Giefing, Maciej; Fornes, Oriol; Vankadari, Naveen; Assi, Salam A.; Costanza, Mariantonia; Weniger, Marc A.; Akalin, Altuna; Anagnostopoulos, Ioannis; Bukur, Thomas; Casarotto, Marco G.; Damm, Frederik; Daumke, Oliver; Edginton-White, Benjamin; Gebhardt, J. Christof M.; Grau, Michael; Grunwald, Stephan; Hansmann, Martin-Leo; Hartmann, Sylvia; Huber, Lionel; Kärgel, Eva; Lusatis, Simone; [...]

Transcriptional reprogramming by mutated IRF4 in lymphoma

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  • Medientyp: E-Artikel
  • Titel: Transcriptional reprogramming by mutated IRF4 in lymphoma
  • Beteiligte: Schleussner, Nikolai; Cauchy, Pierre; Franke, Vedran; Giefing, Maciej; Fornes, Oriol; Vankadari, Naveen; Assi, Salam A.; Costanza, Mariantonia; Weniger, Marc A.; Akalin, Altuna; Anagnostopoulos, Ioannis; Bukur, Thomas; Casarotto, Marco G.; Damm, Frederik; Daumke, Oliver; Edginton-White, Benjamin; Gebhardt, J. Christof M.; Grau, Michael; Grunwald, Stephan; Hansmann, Martin-Leo; Hartmann, Sylvia; Huber, Lionel; Kärgel, Eva; Lusatis, Simone; [...]
  • Erschienen: Springer Science and Business Media LLC, 2023
  • Erschienen in: Nature Communications
  • Sprache: Englisch
  • DOI: 10.1038/s41467-023-41954-8
  • ISSN: 2041-1723
  • Schlagwörter: General Physics and Astronomy ; General Biochemistry, Genetics and Molecular Biology ; General Chemistry ; Multidisciplinary
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>Abstract</jats:title><jats:p>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 &gt; 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.</jats:p>
  • Zugangsstatus: Freier Zugang