Genetic alterations and model of IRF4^mut-mediated pathogenesis in LBCL-IRF4. (A) Fluorescence in situ hybridization with IRF4 break-apart probe shows a signal constellation of 1 colocalization (yellow arrow) and 1 split signal (red and green arrows) consistent with the gene rearrangement in a case with LBCL-IRF4 with pure FL morphology. (B) A diagram of the relative positions of IRF4 mutations in cases with LBCL-IRF4⁴⁴ (A Colmenero, I Salaverria, unpublished data, March 2023). x-axis indicates amino acid position. IRF4 domains: DBD, DNA binding domain; LKD, linker domain; IAD, IRF association domain; and AR, autoinhibitory region. (C) Schematic overview of B-cell differentiation deregulation by constitutive activation of IRF4 and/or NF-κB, which induces the oncogenic transcription program in LBCL-IRF4.