IRF4 mutations in chronic lymphocytic leukemia

Abstract

Interferon regulatory factor 4 (IRF4) is a member of the interferon regulatory factor family of transcription factors and has been shown to have critical functions at several stages of B-cell development. Genome-wide association study identified a polymorphism in the 3' untranslated region of IRF4 as a chronic lymphocytic leukemia risk locus. In this study, we report a recurrent heterozygous somatic mutation in the DNA-binding domain of IRF4 detected in 7 of 457 chronic lymphocytic leukemia patients (1.5%). Patients with IRF4 mutation have a good prognosis, and 4 of 6 have a trisomy 12. We also found that IRF4 mRNA expression is higher in the patients with the mutation.

Figure 1

IRF4 mutations in CLL. (A). Schematic representation of the L116R mutation. (B) Chromatographs of L116R and L116P mutations. (C) Clinical characteristics of patients showing IRF4 mutations. (D) Significantly overexpressed genes in HEK 293 cells transfected with IRF4 L116R versus WT IRF4. (E-F) Mutant and WT IRF4 mRNA levels in CLL samples and transfected HEK 293 cells. (G) Expression of IRF4 L116R mutant increases apoptosis in K562 cells (representative experiment is shown). (H) Expression of IRF4 L116R mutant increases caspase-3/caspase-7 activity in K562 cells. Reaction was stopped at the indicated time points.