Characterizing the Functional Role of IRF4 in Peripheral T-cell Lymphoma Cells
Peripheral T-cell lymphomas (PTCLs) are generally aggressive non-Hodgkin lymphomas with poor overall survival rates following standard therapy. While the possibility of individualized targeted therapy holds promise, advances have been hindered because few therapeutic targets have been identified and validated in PTCLs.
One-third of PTCLs express interferon regulatory factor-4 (IRF4), a tightly-regulated transcription factor involved in lymphocyte growth and differentiation. IRF4 drives tumor growth in several lymphoid malignancies and has been proposed as a candidate therapeutic target. However, direct IRF4 inhibitors are not clinically available
Mayo Clinic researchers, first author Andrew Feldman, M.D., Consultant, Division of Hematopathology at Mayo Clinic, conducted a study recently published in Blood to characterize the functional role of IRF4 in PTCL cells, to identify the mechanisms driving IRF4 expression in PTCL, and to develop a clinically feasible strategy to target those mechanisms.
In the study, Mayo Clinic demonstrated that IRF4 is constitutively expressed in PTCL cells and drives Myc expression and proliferation. Using an inhibitor screen, researchers identified NF-κB as a candidate regulator of IRF4 expression and cell proliferation. They then demonstrated that the NF-κB subunits, p52 and RelB, were transcriptional activators of IRF4. Further analysis showed that activation of CD30 promotes p52 and RelB activity and subsequent IRF4 expression. The study also showed that IRF4 transcriptionally regulates CD30 expression.
Based on this data, the study demonstrate a novel positive feedback loop involving CD30, NF-κB, and IRF4; further evidence for this mechanism was demonstrated in human PTCL tissue samples. Accordingly, NF-κB inhibitors may represent a clinical means to disrupt this feedback loop in IRF4-positive PTCLs.