Mir-22 modulates lenalidomide activity by counteracting myc addiction in multiple myeloma

Daniele Caracciolo, Caterina Riillo, Giada Juli, Francesca Scionti, Katia Todoerti, Nicoletta Polerà, Katia Grillone, Lucia Fiorillo, Mariamena Arbitrio, Maria Teresa Di Martino, Antonino Neri, Pierosandro Tagliaferri, Pierfrancesco Tassone

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article number4365
JournalCancers
Volume13
Issue number17
DOIs
Publication statusPublished - Sep 1 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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