Transcriptional reprogramming by mutated IRF4 in lymphoma

Area of Science:

• Molecular Biology
• Genetics
• Immunology

Background:

• Mutations in transcription factors (TFs) can alter their DNA binding and interactions.
• The impact of TF mutations on composite element (CE) binding and TF interactions remains unclear.
• Perturbed B cell identity in lymphomas, like classic Hodgkin lymphoma, involves altered TF function.

Purpose of the Study:

• To investigate the mechanism of TF alteration in human lymphomas due to mutations.
• To understand how a specific mutation in Interferon Regulatory Factor 4 (IRF4) affects its DNA binding and function.
• To elucidate the role of IRF4 mutations in lymphoma pathogenesis and gene regulation.

Main Methods:

• Analysis of a recurrent somatic missense mutation (c.295T>C, p.Cys99Arg; p.C99R) in the IRF4 DNA-binding domain.
• Assessment of IRF4 DNA-binding specificity to canonical and non-canonical motifs and composite elements (CEs).
• Evaluation of IRF4 function in plasma cell induction and regulation of disease-specific genes.

Main Results:

• The IRF4-C99R mutation alters DNA binding, causing loss of binding to canonical IRF motifs.
• IRF4-C99R exhibits neomorphic gain-of-binding to canonical and non-canonical IRF CEs.
• IRF4-C99R blocks IRF4-dependent plasma cell induction and up-regulates disease-specific genes via an AP-1-IRF-CE (AICE) dependent manner.

Conclusions:

• A single mutation in IRF4 can cause a complex switch in TF specificity and gene regulation.
• The study explains how IRF4 mutations contribute to lymphoma development by altering TF function.
• Targeting neomorphic DNA-binding activities of mutant TFs presents a potential therapeutic strategy.