Schlafen 11 Is Overexpressed in Multiple Myeloma and Undergoes Nucleolar Translocation in Response to Bortezomib.

UNLABELLED: Proteins belonging to the Schlafen family are interferon-inducible and participate in the regulation of antiviral responses, immune signaling, and proteotoxic stress. Schlafen 11 (SLFN11) also kills cells with replicative damage, serving as a predictive biomarker for chemotherapeutic response. In this study, we examined SLFN11 expression and significance in multiple myeloma. The Cancer Genome Atlas and MMRF CoMMpass datasets were analyzed for SLFN11 expression. Bone marrow and cell lines samples were analyzed for SLFN11 protein. SLFN11-knockout multiple myeloma cell lines were used to explore how SLFN11 affects bortezomib (BTZ) response. Retrospective analysis of the HOVON-65/GMMG-HD4 phase III trial (n = 327) assessed clinical relevance. SLFN11 is consistently highly expressed across multiple myeloma subtypes (except CD1 and MAF/MAFB) and in normal plasma cells, and its expression strongly correlates with super-enhancer-driven plasma cell transcriptional programs. CD138-positive normal and myeloma plasma cells retain SLFN11 expression even when proliferative activity (MKI67/Ki-67) increases with disease progression. BTZ, a first-line multiple myeloma treatment, induces SLFN11 nucleolar translocation with suppression of ribosomal RNA (rRNA) synthesis. Knocking out SLFN11 in multiple myeloma cells enhances BTZ sensitivity and exatecan resistance, supporting SLFN11's protective role in proteotoxic stress and sensitizing role in replication stress. In the HOVON-65/GMMG-HD4 trial, SLFN11-low patients seemed to preferentially benefit from BTZ-based therapy, suggesting that SLFN11 expression may guide therapeutic stratification in multiple myeloma.

SIGNIFICANCE: SLFN11 is highly expressed in normal and malignant plasma cells. BTZ induces SLFN11 nucleolar translocation, suppressing rRNA synthesis. SLFN11 confers BTZ resistance while sensitizing to topoisomerase I inhibitors. Low SLFN11 expression may identify patients more likely to benefit from BTZ-based therapy, providing a mechanistic rationale for SLFN11-guided therapeutic stratification.