Interferon regulatory factor 4 (IRF4) (IRF4)

Interferon regulatory factor 4 (IRF4) is a lymphoid-specific transcription factor that serves as a master regulator of B-cell to plasma cell differentiation and T-cell polarization (UniProt P51844). In hematologic malignancies, particularly multiple myeloma, IRF4 is characterized as a lineage-addiction factor; its expression is essential for the survival of myeloma cells, forming a feedback loop with MYC to drive oncogenesis (Shaffer et al., Nature 2008). While the IRF4 protein lacks a traditional small-molecule binding pocket, its mRNA has become a high-priority therapeutic target. Antisense oligonucleotides (ASOs), such as ION251 (IONIS-IRF4-LRx), are designed to bind specifically to human IRF4 mRNA, triggering its degradation via RNase H and subsequently depleting the IRF4 protein (ClinicalTrials.gov NCT03701282). Clinically, IRF4 levels are also modulated indirectly by immunomodulatory drugs (IMiDs) like lenalidomide, which induce the degradation of Ikaros and Aiolos, the primary transcriptional activators of IRF4 (Kronke et al., Science 2014). Therapeutic challenges include potential myelosuppression and impaired normal immune function, given IRF4's role in healthy lymphocyte biology.

Other names

MUM1Multiple myeloma oncogene 1LSIRFNF-AT-induced antigen 71

Antisense oligonucleotide-mediated degradation of mRNA via RNase H recruitment; indirect transcriptional downregulation via E3 ubiquitin ligase-mediated degradation of Ikaros and Aiolos.