ISG20L2 suppresses bortezomib antimyeloma activity by attenuating bortezomib binding to PSMB5
Yan Yang, Yuhan Gao, Jingcao Huang, Zhuang Yang, Hongmei Luo, Fangfang Wang, Juan Xu, Yushan Cui, Hong Ding, Zhimei Lin, Xinyu Zhai, Ying Qu, Li Zhang, Ting Liu, Lingqun Ye, Ting Niu, Yuhuan Zheng
Yan Yang, Yuhan Gao, Jingcao Huang, Zhuang Yang, Hongmei Luo, Fangfang Wang, Juan Xu, Yushan Cui, Hong Ding, Zhimei Lin, Xinyu Zhai, Ying Qu, Li Zhang, Ting Liu, Lingqun Ye, Ting Niu, Yuhuan Zheng
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Research Article Hematology

ISG20L2 suppresses bortezomib antimyeloma activity by attenuating bortezomib binding to PSMB5

Abstract

The proteasome inhibitors (PIs) bortezomib and carfilzomib, which target proteasome 20S subunit beta 5 (PSMB5) in cells, are widely used in multiple myeloma (MM) treatment. In this study, we demonstrated the role of interferon-stimulated 20 kDa exonuclease-like 2 (ISG20L2) in MM PI resistance. Gain- and loss-of-function studies showed that ISG20L2 suppressed MM cell sensitivity to PIs in vitro and in vivo. Patients with ISG20L2lo MM had a better response to PIs and a longer overall survival than patients with ISG20L2hi MM. Biotinylated bortezomib pull-down assays showed that ISG20L2 competed with PSMB5 in binding to bortezomib. The surface plasmon resonance assay confirmed the direct binding of bortezomib to ISG20L2. In ISG20L2hi MM cells, ISG20L2 attenuated the binding of bortezomib to PSMB5, resulting in lower inhibition of proteasome activity and therefore less bortezomib-induced cell death. Overall, we identified a potentially novel mechanism by which ISG20L2 conferred bortezomib resistance on MM. The expression of ISG20L2 correlated with MM PI responses and patient treatment outcomes.

Authors

Yan Yang, Yuhan Gao, Jingcao Huang, Zhuang Yang, Hongmei Luo, Fangfang Wang, Juan Xu, Yushan Cui, Hong Ding, Zhimei Lin, Xinyu Zhai, Ying Qu, Li Zhang, Ting Liu, Lingqun Ye, Ting Niu, Yuhuan Zheng

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Figure 1

Identification of ISG20L2 as an overexpressed gene in +1q myeloma.

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Identification of ISG20L2 as an overexpressed gene in +1q myeloma. (A) W...
(A) Western blot showing the expression of ISG20L2 in 5 human MM cell lines (OCI-My5, IM-9, AMO1, ARD, KMS-11). (B) In the MM patient gene expression data set GEO GSE2658, the expression of ISG20L2 in primary MM cells increased with the copy number of 1q21 (n = 248; patients with 2 copies = 134, patients with 3 copies = 70, patients with 4 or more copies = 44). One-way ANOVA with a post hoc least significant difference (LSD) t test was performed. P values: **P ≤ 0.01; ****P ≤ 0.0001. (C) Real-time quantitative PCR (RT-qPCR) results showed ISG20L2 expression in primary MM cells of 76 patients diagnosed at West China Hospital (WCH). The 1q amplification status of patients was determined by FISH assay. Student’s t test was performed. ****P ≤ 0.0001. (D) Dot blot assay of ISG20L2 in the 61 patients with MM mentioned in C (left blots). The dot intensities of ISG20L2 relative to GAPDH were calculated (right column). Student’s t test was performed. ****P ≤ 0.0001. Box plots show the interquartile range (box), median (line), and minimum and maximum (whiskers). (E) In MM patient gene expression data sets GSE9782 (left, n = 264) and GSE2658 (right, n = 559), Kaplan-Meier curves showed the correlation between ISG20L2 expression and overall survival (OS) in patients with MM. P values were calculated by Mantel-Cox test. (F) In the GSE13591 data set (n = 186), Kaplan-Meier curves showed the survival of different MM patient groups. P values were calculated by Mantel-Cox test.