1. Transcriptional reprogramming by mutated IRF4 in lymphoma.
- Author
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Schleussner N, Cauchy P, Franke V, Giefing M, Fornes O, Vankadari N, Assi SA, Costanza M, Weniger MA, Akalin A, Anagnostopoulos I, Bukur T, Casarotto MG, Damm F, Daumke O, Edginton-White B, Gebhardt JCM, Grau M, Grunwald S, Hansmann ML, Hartmann S, Huber L, Kärgel E, Lusatis S, Noerenberg D, Obier N, Pannicke U, Fischer A, Reisser A, Rosenwald A, Schwarz K, Sundararaj S, Weilemann A, Winkler W, Xu W, Lenz G, Rajewsky K, Wasserman WW, Cockerill PN, Scheidereit C, Siebert R, Küppers R, Grosschedl R, Janz M, Bonifer C, and Mathas S
- Subjects
- Humans, B-Lymphocytes metabolism, DNA, Gene Expression Regulation, Interferon Regulatory Factors genetics, Interferon Regulatory Factors metabolism, Lymphoma genetics
- 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., (© 2023. The Author(s).)
- Published
- 2023
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