Increased CSN5 expression enhances the sensitivity to lenalidomide in multiple myeloma cells

Lenalidomide (LEN) is commonly used as an effective therapeutic agent for multiple myeloma (MM). However, in some patients, primary resistance to LEN is observed, the mechanisms of which remain poorly understood. In this study, we combined a LEN sensitivity assay with proteomics data from 15 MM cell lines to identify protein expression profiles associated with primary LEN resistance. Our findings revealed that CSN5 expression is lower in LEN-resistant cell lines than in LEN-sensitive lines. Moreover, we established that CSN5 is degraded via the cullin-RING ubiquitin ligase (CRL)-mediated ubiquitin-proteasome pathway through ubiquitination at lysine 194. Our data suggest that reduced CSN5 expression leads to abnormalities in the ubiquitination cycle of CRL4A, resulting in the inhibition of LEN-mediated degradation of IKZF1 and IKZF3. These findings delineate an additional mechanism of LEN resistance in MM cells and may contribute to the development of alternative therapeutic strategies to overcome LEN resistance.