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Transcriptional reprogramming by mutated IRF4 in lymphoma

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Item Type:Article
Title:Transcriptional reprogramming by mutated IRF4 in lymphoma
Creators Name:Schleussner, N. and Cauchy, P. and Franke, V. and Giefing, M. and Fornes, O. and Vankadari, N. and Assi, S.A. and Costanza, M. and Weniger, M.A. and Akalin, A. and Anagnostopoulos, I. and Bukur, T. and Casarotto, M.G. and Damm, F. and Daumke, O. and Edginton-White, B. and Gebhardt, J.C.M. and Grau, M. and Grunwald, S. and Hansmann, M.L. and Hartmann, S. and Huber, L. and Kärgel, E. and Lusatis, S. and Noerenberg, D. and Obier, N. and Pannicke, U. and Fischer, A. and Reisser, A. and Rosenwald, A. and Schwarz, K. and Sundararaj, S. and Weilemann, A. and Winkler, W. and Xu, W. and Lenz, G. and Rajewsky, K. and Wasserman, W.W. and Cockerill, P.N. and Scheidereit, C. and Siebert, R. and Küppers, R. and Grosschedl, R. and Janz, M. and Bonifer, C. and Mathas, S.
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.
Keywords:B-Lymphocytes, DNA, Gene Expression Regulation, Interferon Regulatory Factors, Lymphoma
Source:Nature Communications
Publisher:Nature Publishing Group
Page Range:6947
Date:7 November 2023
Official Publication:https://doi.org/10.1038/s41467-023-41954-8
PubMed:View item in PubMed

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