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bioRxiv · 10.64898/2026.02.06.704297

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

Arakawa, Y.·Taniyama, D.·Suzuki, K.·Yano, S.·Pommier, Y.
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Abstract

Proteins belonging to the Schlafen family are interferon-inducible and participate in the regulation of antiviral responses, immune signaling and proteotoxic stress. SLFN11 also kills cells with replicative damage, serving as a predictive biomarker for chemotherapeutic response. Here we examined SLFN11 expression and significance in multiple myeloma (MM). The TCGA and MMRF CoMMpass datasets were analyzed for SLFN11 expression. Bone marrow and cell lines samples were analyzed for SLFN11 protein. SLFN11-knockout MM cell lines were used to explore how SLFN11 affects bortezomib response. Retrospective analysis of the HOVON-65/GMMG-HD4 phase III trial (n=327) assessed clinical relevance. SLFN11 is consistently highly expressed across MM 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. Bortezomib, a first-line MM treatment, induces SLFN11 nucleolar translocation with suppression of ribosomal RNA synthesis. Knocking out SLFN11 in MM cells enhances bortezomib sensitivity and exatecan resistance, supporting SLFN11s protective role in proteotoxic stress and sensitizing role in replication stress. In the HOVON-65/GMMG-HD4 trial, SLFN11-low patients showed selective benefit from bortezomib-based therapy, suggesting that SLFN11 expression may guide therapeutic stratification in MM. SignificanceSLFN11 is highly expressed in normal and malignant plasma cells. Bortezomib induces SLFN11 nucleolar translocation, suppressing ribosomal RNA synthesis and global translation. SLFN11 confers bortezomib resistance while sensitizing to topoisomerase I inhibitors. Clinical analysis supports that low SLFN11 expression predicts bortezomib benefit, providing a mechanistic basis for SLFN11-guided therapeutic stratification.

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Arakawa, Y., Taniyama, D., Suzuki, K., Yano, S., Pommier, Y.. 2026-02-07. Schlafen 11 (SLFN11) overexpression and nucleolar localization in response to bortezomib in multiple myeloma. https://doi.org/10.64898/2026.02.06.704297

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