IRF4 mediates non-enzymatic dependency on IRE1 in Multiple Myeloma cells

Multiple Myeloma (MM) arises through oncogenic transformation of immunoglobulin-secreting plasma cells. MM often co-opts the endoplasmic-reticulum (ER) stress mitigator, inositol-requiring enzyme 1 (IRE1) to sustain malignant growth. While certain MMs require enzymatic IRE1-dependent activation of the ER-homeostatic transcription factor XBP1s, others display a non-enzymatic dependency on IRE1 that is not yet mechanistically understood. Interferon regulatory factor 4 (IRF4) stimulates gene programs that promote immune-cell proliferation and plays an essential role in MM. Here we show that the non-enzymatic reliance on IRE1 in MM entails IRF4. IRE1 silencing increased inhibitory phosphorylation of IRF4, disrupting its chromatin-binding activity and mRNA transcription. IRF4 knockdown recapitulated, whereas IRF4 re-expression reversed the anti-proliferative phenotype of IRE1 silencing. Mechanistic studies revealed that IRF4 engages the E2F1 and CDC25A genes and promotes CDK2 activation to drive cell cycle progression. Our results uncover an unexpected functional link between IRE1 and IRF4 in MM.