miR-22 Modulates Lenalidomide Activity by Counteracting MYC Addiction in Multiple Myeloma

Background: MYC is a master regulator of multiple myeloma (MM) by orchestrating several pro-tumoral pathways, including reprograming of the miRNA transcriptome. MYC is also involved in the acquirement of resistance to anti-MM drugs, including immunomodulatory imidedrugs (IMiDs). Methods: In silico analysis was performed on MM proprietary and on public MMRFCoMMpass datasets. Western blot and chromatin immunoprecipitation (ChIP) experiments wereperformed to validate miR-22 repression induced by MYC. Cell viability and apoptosis assays wereused to evaluate lenalidomide sensitization after miR-22 overexpression. Results: We found an inverse correlation between MYC and miR-22 expression, which is associated with poor outcome inIMiD-treated MM patients. Mechanistically, we showed that MYC represses transcription of miR22, which, in turn, targets MYC, thus establishing a feed-forward loop. Interestingly, we found thatIMiD lenalidomide increases miR-22 expression by reducing MYC repression and, most importantly, that the combination of lenalidomide with miR-22 mimics results in a synergistic directand NK-mediated cytotoxic activity. Conclusions: Taken together, our findings indicate that: (1) lowmiR-22 expression could represent a potential predictive biomarker of poor lenalidomide responsein MM patients; and (2) miR-22 reduces MYC oncogenic activity, thus triggering a novel syntheticlethality loop, which sensitizes MM cells to lenalidomide.