A new type of pathogenic transcription factor mutation targeting interferon regulatory factor 4 (IRF4) in human lymphoma

We report the characterization of a recurrent somatic mutation c.295T>C (p.C99R) in the Interferon Regulatory Factor 4 (IRF4) gene in human lymphoma in the a3-recognition helix of the IRF4 DNA-binding domain. IRF4-C99R fundamentally alters IRF4 DNA-binding, combining loss-of-binding at canonical IRF motifs and neomorph gain-of-binding at canonical and non-canonical IRF composite elements (CEs). IRF4-C99R thoroughly modifies IRF4 function, blocking IRF4-dependent plasma cell induction, and specifically up-regulating lymphoma-specific genes in a degenerate Activator Protein-1 (AP-1)-IRF-CE (AICE)-dependent manner.