학술논문
Transcriptional reprogramming by mutated IRF4 in lymphoma
Document Type
article
Author
Nikolai Schleussner; Pierre Cauchy; Vedran Franke; Maciej Giefing; Oriol Fornes; Naveen Vankadari; Salam A. Assi; Mariantonia Costanza; Marc A. Weniger; Altuna Akalin; Ioannis Anagnostopoulos; Thomas Bukur; Marco G. Casarotto; Frederik Damm; Oliver Daumke; Benjamin Edginton-White; J. Christof M. Gebhardt; Michael Grau; Stephan Grunwald; Martin-Leo Hansmann; Sylvia Hartmann; Lionel Huber; Eva Kärgel; Simone Lusatis; Daniel Noerenberg; Nadine Obier; Ulrich Pannicke; Anja Fischer; Anja Reisser; Andreas Rosenwald; Klaus Schwarz; Srinivasan Sundararaj; Andre Weilemann; Wiebke Winkler; Wendan Xu; Georg Lenz; Klaus Rajewsky; Wyeth W. Wasserman; Peter N. Cockerill; Claus Scheidereit; Reiner Siebert; Ralf Küppers; Rudolf Grosschedl; Martin Janz; Constanze Bonifer; Stephan Mathas
Source
Nature Communications, Vol 14, Iss 1, Pp 1-18 (2023)
Subject
Language
English
ISSN
2041-1723
Abstract
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.