IRF4 (MUM1) in B-cell malignancies: molecular mechanisms, biological functions, and clinical implications

Interferon regulatory factor 4 (IRF4), also known as multiple myeloma oncogene 1 (MUM1), is a member of the IRF family of transcription factors with pivotal roles in the immune system, particularly in B-lymphocyte lineage commitment, differentiation, and immune regulation. Unlike other IRFs, IRF4 expression is tightly regulated by immune microenvironmental signals rather than classical interferon pathways. In B-lymphocytes, IRF4 orchestrates critical steps of development, including pre-B-cell differentiation, germinal centre formation, and terminal plasma cell maturation. Its dosage- and context-dependent functions regulate gene networks pivotal for both normal immunity and antibody production, with loss of function resulting in profound immunodeficiency. Recent genomic and molecular studies have revealed that IRF4 is central to the pathogenesis of multiple B-cell malignancies. Acting either as a tumour suppressor in B-cell precursor acute lymphoblastic leukaemia or as an oncogenic driver in diseases such as activated B-cell-like diffuse large B-cell lymphoma, and especially in multiple myeloma (MM), IRF4 modulates transcriptional programs responsible for proliferation, survival, and resistance to therapy. Chromosomal translocations, somatic mutations, and aberrant activation of IRF4 regulatory networks underpin disease progression and heterogeneity. Given its multifaceted roles, IRF4 is emerging as a critical biomarker, prognostic factor, and therapeutic target in B-cell disorders. This review synthesises current advances in IRF4 biology and pathology, highlighting promising therapeutic strategies that disrupt IRF4-driven molecular circuits. Continued elucidation of IRF4's diverse functions will pave the way for precision medicine initiatives in B-lymphoid malignancies.