Regulatory network of BLIMP1, IRF4, and XBP1 triad in plasmacytic differentiation and multiple myeloma pathogenesis

Antibody secreting plasma cell plays an indispensable role in humoral immunity. As activated B cell undergoes germinal center reaction and develops into plasma cell, it gradually loses B cell characteristics and embraces functional changes associated with immunoglobulins production. Differentiation of B cell into plasma cell involves drastic changes in cell structure, granularity, metabolism, gene expression and epigenetic regulation that couple with the mounting capacity for synthesis of a large quantity of antigen-specific antibodies. The interplay between three hallmark transcriptional regulators IRF4, BLIMP1, and XBP1, is critical for supporting the cellular reprograming activities during B to plasma cell transition. IRF4 promotes plasma cell generation by directing immunoglobulin class switching, proliferation and survival; BLIMP1 serves as a transcriptional repressor that extinguishes B cell features; whereas XBP1 controls unfolded protein response that relieves endoplasmic reticulum stress and permits antibody release during terminal differentiation. Intriguingly, high expression of IRF4, BLIMP1, and XBP1 molecules have been reported in myeloma cells derived from multiple myeloma patients, which negatively impact treatment outcome, prognosis, and relapse frequency. Despite the introduction of immunomodulatory drugs in recent years, multiple myeloma is still an incurable disease with poor survival rate. An in-depth review of IRF4, BLIMP1, and XBP1 triad molecules in plasma cell generation and multiple myeloma tumorigenesis may provide clues to the possibility of targeting these molecules in disease management.