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 imide drugs (IMiDs). Methods: In silico analysis was performed on MM proprietary and on public MMRFCoMMpass datasets. Western blot and chromatin immunoprecipitation (ChIP) experiments were performed to validate miR-22 repression induced by MYC. Cell viability and apoptosis assays were used 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 in IMiD-treated MM patients. Mechanistically, we showed that MYC represses transcription of miR-22, which, in turn, targets MYC, thus establishing a feed-forward loop. Interestingly, we found that IMiD 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 direct and NK-mediated cytotoxic activity. Conclusions: Taken together, our findings indicate that: (1) low miR-22 expression could represent a potential predictive biomarker of poor lenalidomide response in MM patients; and (2) miR-22 reduces MYC oncogenic activity, thus triggering a novel synthetic lethality loop, which sensitizes MM cells to lenalidomide.
MiR-22 modulates lenalidomide activity by counteracting myc addiction in multiple myeloma / D. Caracciolo, C. Riillo, G. Juli, F. Scionti, K. Todoerti, N. Polera, K. Grillone, L. Fiorillo, M. Arbitrio, M.T. Di Martino, A. Neri, P. Tagliaferri, P. Tassone. - In: CANCERS. - ISSN 2072-6694. - 13:17(2021), pp. 4365.1-4365.20. [10.3390/cancers13174365]
|Titolo:||MiR-22 modulates lenalidomide activity by counteracting myc addiction in multiple myeloma|
|Parole Chiave:||MYC; NK cells; lenalidomide; miR-22; microRNA; multiple myeloma|
|Settore Scientifico Disciplinare:||Settore MED/15 - Malattie del Sangue|
|Data di pubblicazione:||2021|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.3390/cancers13174365|
|Appare nelle tipologie:||01 - Articolo su periodico|