Superenhancer-driven SMC4 promotes myeloma growth by epigenetically enhancing IFI16-dependent STING signaling

Multiple myeloma (MM) is a complex hematological malignancy characterized by the uncontrolled proliferation of plasma cells in the bone marrow. Emerging evidence suggests that the aberrant activation of specific gene regulatory elements known as SE plays a crucial role in driving oncogenic gene expression programs in cancer. In this study, we investigated the role of the SE-driven SMC4 in promoting myeloma growth. Depletion of SMC4 resulted in a significant impairment of myeloma cell proliferation and clonogenicity. Mechanistically, we identified that SMC4 orchestrates the epigenetic modulation of the IFI16-dependent STING signaling pathway. This epigenetic enhancement of the IFI16-STING axis led to increased production of pro-inflammatory cytokines, creating a favorable microenvironment for myeloma cell growth. Furthermore, we established a direct link between the SE-driven SMC4 and the upregulation of IFI16 and STING gene expression in MM cells. Importantly, pharmacological inhibition of the IFI16-STING pathway abrogated the oncogenic effects mediated by SMC4. Our findings uncover a novel regulatory circuit involving SMC4 and the IFI16-STING signaling axis that promotes myeloma growth. Targeting this epigenetic network may hold therapeutic potential to intervene in myeloma progression and improve patient outcomes.