ISG20L2 Suppresses Bortezomib Anti-Myeloma Activity By Attenuating Bortezomib Binding to PSMB5

Proteasome inhibitors (PIs) bortezomib and carfilzomib, which target proteasome 20S subunit beta5 (PSMB5) in cells, are widely used in multiple myeloma (MM) treatment. In this study, we demonstrated the role of interferon-stimulated 20kD exonuclease-like 2 (ISG20L2) in MM PI-resistance. Gain- and loss-of-function studies showed that ISG20L2 suppressed MM cells' sensitivity to PIs in vitro and in vivo. Patients with ISG20L2^low MM had a better response to PIs and a longer overall survival than patients with ISG20L2^high MM. Biotinylated-bortezomib pull-down assays showed that ISG20L2 competed with PSMB5 in binding to bortezomib. Surface plasmon resonance assays further confirmed the direct binding of bortezomib or carfilzomib to ISG20L2. In ISG20L2^high MM cells, ISG20L2 attenuated the binding of bortezomib to PSMB5, resulting lower inhibition of proteasome activity and therefore lesser bortezomib-induced cell death. Overall, we identified a novel mechanism which ISG20L2 conferred bortezomib resistance on MM. The expression of ISG20L2 correlated with the MM PI responses and the patients' treatment outcome.

No relevant conflicts of interest to declare.