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An Organotypic High Throughput System for Characterization of Drug Sensitivity of Primary Multiple Myeloma Cells
Published on: July 15, 2015
Schlafen 11 (SLFN11) overexpression and nucleolar localization in response to bortezomib in multiple myeloma
Yasuhiro Arakawa1,2,3, Daiki Taniyama1, Kazuhito Suzuki2
1Laboratory of Molecular Pharmacology and Developmental Therapeutics Branch, Center for Cancer Research, NCI, NIH.
Abstract:
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.
Insights
Schlafen family member 11 (SLFN11) is highly expressed in multiple myeloma (MM) and influences treatment response. It confers resistance to bortezomib but sensitivity to other therapies, acting as a dual biomarker.
Area of Science:
- Immunology
- Molecular Biology
- Oncology
Background:
- Schlafen family proteins, including SLFN11, are interferon-inducible and involved in antiviral responses, immune signaling, and proteotoxic stress.
- SLFN11 acts as a biomarker for chemotherapeutic response by inducing cell death in replicative damage and is epigenetically downregulated in many solid tumors.
Purpose of the Study:
- To investigate the expression and significance of SLFN11 in multiple myeloma (MM).
- To determine SLFN11's role in MM pathogenesis and its potential as a therapeutic biomarker.
Main Methods:
- Analysis of TCGA and MMRF CoMMpass datasets for SLFN11 expression in MM subtypes.
- Correlation analysis of SLFN11 expression with disease progression markers (MKI67/Ki-67) and transcriptional programs.
- Experimental investigation of SLFN11's response to bortezomib, including nucleolar translocation and ribosomal RNA synthesis suppression.
- Assessment of SLFN11 knockout cells' sensitivity to bortezomib and exatecan.
Main Results:
- SLFN11 is highly expressed across most MM subtypes, with retained expression in plasma cells despite increased proliferation.
- SLFN11 expression correlates with super-enhancer-driven plasma cell transcriptional programs.
- Bortezomib treatment induces SLFN11 nucleolar accumulation and suppresses ribosomal RNA synthesis.
- SLFN11 knockout enhances bortezomib sensitivity but confers exatecan resistance, indicating a dual role in stress response.
Conclusions:
- SLFN11 plays a significant role in multiple myeloma, influencing cellular responses to proteasome inhibition and replication stress.
- SLFN11's nucleolar translocation and suppression of rRNA synthesis upon bortezomib treatment contribute to treatment resistance.
- SLFN11 functions as a dual biomarker, predicting resistance to bortezomib and sensitivity to topoisomerase I inhibitors, aiding precision therapy selection in MM.
