Transcriptional reprogramming by mutated IRF4 in lymphoma

Autor/innen

  • N. Schleussner
  • P. Cauchy
  • V. Franke
  • M. Giefing
  • O. Fornes
  • N. Vankadari
  • S.A. Assi
  • M. Costanza
  • M.A. Weniger
  • A. Akalin
  • I. Anagnostopoulos
  • T. Bukur
  • M.G. Casarotto
  • F. Damm
  • O. Daumke
  • B. Edginton-White
  • J.C.M. Gebhardt
  • M. Grau
  • S. Grunwald
  • M.L. Hansmann
  • S. Hartmann
  • L. Huber
  • E. Kärgel
  • S. Lusatis
  • D. Noerenberg
  • N. Obier
  • U. Pannicke
  • A. Fischer
  • A. Reisser
  • A. Rosenwald
  • K. Schwarz
  • S. Sundararaj
  • A. Weilemann
  • W. Winkler
  • W. Xu
  • G. Lenz
  • K. Rajewsky
  • W.W. Wasserman
  • P.N. Cockerill
  • C. Scheidereit
  • R. Siebert
  • R. Küppers
  • R. Grosschedl
  • M. Janz
  • C. Bonifer
  • S. Mathas

Journal

  • Nature Communications

Quellenangabe

  • Nat Commun 14 (1): 6947

Zusammenfassung

  • 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.


DOI

doi:10.1038/s41467-023-41954-8