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IRF4 requires ARID1A to establish plasma cell identity in multiple myeloma

ABSTRACT: Multiple myeloma (MM) is an incurable malignancy of plasma cells that exploits transcriptional networks driven by IRF4. To discover unique molecular vulnerabilities in MM centered on IRF4, 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. Deletion of Arid1a in activated murine B cells thwarts subsequent plasma cell differentiation by disrupting IRF4-dependent transcriptional networks, therefore 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 amplification of oncogenic gene expression driven by MYC, resulting in profound toxicity to MM cells. Notably, MM patients with aggressive disease have markers of SWI/SNF activity, 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 to effectively treat this incurable disease.

INSTRUMENT(S): Orbitrap Eclipse

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

SUBMITTER: Ryan Young

PROVIDER: MSV000093842 | MassIVE | Thu Jan 11 12:58:00 GMT 2024

REPOSITORIES: MassIVE

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

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