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 3

ISG20L2 expression correlates with the response of patients with MM to PIs.

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ISG20L2 expression correlates with the response of patients with MM to P...
(A) In data set GSE9782, 169 patients with MM received BTZ treatment. We analyzed ISG20L2 expression in patients with MM who responded to BTZ treatment (R, n = 85, ISG20L2 expression: 8.009 to 351.6, median value = 118.6) and who did not respond to BTZ treatment (NR, n = 84, ISG20L2 expression: 13.89 to 443.7, median value = 134.5). Student’s t test was performed. *P ≤ 0.05. (B) In the MMRF CoMMpass data set, analyses of the correlation between ISG20L2 expression and patients’ response status to PIs (BTZ or CFZ) treatment. Patients were stratified based on response degrees after treatment as CR (n = 176, ISG20L2 expression: 7.612 to 64.42, median value = 24.83), VGPR (n = 344, ISG20L2 expression: 4.044 to 98.31, median value = 21.94), PR (n = 100, ISG20L2 expression: 5.433 to 56.73, median value = 21.07), SD (n = 33, ISG20L2 expression: 12.84 to 56.51, median value = 27.83) and PD (n = 6, ISG20L2 expression: 16.14 to 68.98, median value = 33.86). One-way ANOVA with post hoc LSD t test was performed. *P ≤ 0.05; **P ≤ 0.01. (C) In the MMRF CoMMpass data set, for the patients who received PI treatment, ISG20L2 expression was analyzed in patients without PD (n = 376, ISG20L2 expression: 4.044 to 108.9, median value = 20.88) and in patients with at least 1 PD (n = 287, ISG20L2 expression: 6.284 to 98.31, median value = 25.33). Student’s t test was performed. ****P ≤ 0.0001. (D) In the MMRF CoMMpass data set, for the patients who received PI-based therapy and died from disease progression, 20 patients had sequential BM gene expression profile data. ISG20L2 expression increased during the treatment. Student’s t test was performed. *P ≤ 0.05.