IRF4 requires ARID1A to establish plasma cell identity in multiple myeloma (CUT&RUN human 6)

Multiple myeloma (MM) is an incurable malignancy of plasma cells that exploits transcriptional networks underpinning normal plasma cell biology to drive malignant growth and survival. The transcription factor IRF4 serves as the principal architect of plasma cell identity, and MM cells are addicted to IRF4 expression for their survival. To discover unique molecular vulnerabilities in MM, we employ a multi-omics approach integrating functional genomics screening, spatial-proteomics, and global chromatin mapping. We find that ARID1A, a member of the SWI/SNF chromatin remodeling complex, is both required for IRF4 expression and functionally associated with IRF4 protein on chromatin. Conditional deletion of Arid1a in activated murine B cells thwarts subsequent plasma cell differentiation by disrupting IRF4-dependent transcriptional networks, thus defining ARID1A as a novel plasma cell vulnerability. Targeting ARID1A-dependent SWI/SNF activity via SMARCA2/4 inhibition induces a rapid loss of IRF4-target gene expression and quenches global oncogenic amplification of gene expression driven by MYC, resulting in profound toxicity to MM cells. Notably, SWI/SNF-dependent genes are upregulated in MM patients with aggressive disease, and SMARCA2/4 inhibitors retain their activity in immunomodulatory drug (IMiD)-resistant MM cells. To fully harness the potential of these drugs, we use combinatorial drug screens to uncover profound synergistic toxicity between SMARCA2/4 and MEK inhibitors. Thus, targeting SWI/SNF activity potently represses an IRF4-MYC feed forward loop and provides a feasible path forward to effectively treat this incurable disease.