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- Title
Transcriptional reprogramming by mutated IRF4 in lymphoma.
- Authors
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
- 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. Cancer is often associated with mutant transcription factors (TFs) but their functional characterization is challenging. Here, the authors describe a recurrent mutation within TF IRF4 in human lymphomas and they show how it causes a complex switch in TF specificity and functionality.
- Subjects
INTERFERON regulatory factors; HODGKIN'S disease; MISSENSE mutation; GENETIC regulation; TRANSCRIPTION factors
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-41954-8