Schlafen 11 (SLFN11) overexpression and nucleolar localization in response to bortezomib in multiple myeloma.

Proteins belonging to the Schlafen family are interferon-inducible and participate in the regulation of antiviral responses, immune signaling, and proteotoxic stress. SLFN11 kills cells with replicative damage, serving as a predictive biomarker for chemotherapeutic response. SLFN11 is epigenetically downregulated in ≈50% of solid tumors. Here we examined SLFN11 expression and significance in multiple myeloma (MM). Using TCGA and MMRF CoMMpass datasets, we find SLFN11 is consistently highly expressed across MM subtypes except CD1 and MAF/MAFB. CD138-positive normal and myeloma plasma cells retain SLFN11 expression even when proliferative activity (MKI67/Ki-67) increases with disease progression. SLFN11 expression strongly correlates with super-enhancer-driven plasma cell transcriptional programs. We report that bortezomib, a first-line MM treatment, induces SLFN11 accumulation in nucleoli with suppression of ribosomal RNA synthesis. SLFN11 knockout cells show enhanced bortezomib sensitivity and exatecan resistance, supporting SLFN11's protective role in proteotoxic stress and sensitizing role in replication stress. This study reveals that SLFN11 undergoes nucleolar translocation in response to proteasome inhibition in multiple myeloma, suppressing ribosomal RNA synthesis and conferring resistance to bortezomib while maintaining sensitivity to topoisomerase I inhibitors, thereby establishing SLFN11 as a dual-function biomarker for precision therapy selection in this disease.