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IRF4 mediates nonenzymatic dependency on IRE1 in Multiple 1 Myeloma cells

ABSTRACT: 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 nonenzymatic dependency on IRE1 that is not yet mechanistically understood. Interferon regulatory factor 4 (IRF4) stimulates gene programs that promote immune-cell proliferation and cell cycle control by IRE1 in MM. Here we show that IRF4 acts as a key conduit of nonenzymatic cell cycle control by IRE1 in MM. IRE1 silencing increased inhibitory phosphorylation of IRF4, disrupting its chromatin-binding activity and mRNA transcription. IRF4 knockdown recapitulated, whereas IRF4 repletion reversed the anti-proliferative phenotype of IRE1 silencing. Functional studies revealed that IRF4 engages the E2F1 and CDC25A genes and promotes CDK2 activation to drive cell cycle progression. Our results advance mechanistic understanding of IRE1 and IRF4 in MM.

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Avi Ashkenazi

PROVIDER: MSV000095907 | MassIVE |

REPOSITORIES: MassIVE

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