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Article

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

1
Department of Experimental and Clinical Medicine, Magna Græcia University, 88100 Catanzaro, Italy
2
Institute of Research and Biomedical Innovation (IRIB), Italian National Council (CNR), 98164 Messina, Italy
3
Hematology, Fondazione Cà Granda IRCCS Policlinico, 20019 Milan, Italy
4
Institute of Research and Biomedical Innovation (IRIB), Italian National Council (CNR), 88100 Catanzaro, Italy
5
Department of Oncology and Hemato-Oncology, University of Milan, 20019 Milan, Italy
*
Author to whom correspondence should be addressed.
These authors equally contributed to the work.
Academic Editor: Meletios-Athanasios Dimopoulos
Cancers 2021, 13(17), 4365; https://doi.org/10.3390/cancers13174365
Received: 4 August 2021 / Revised: 21 August 2021 / Accepted: 24 August 2021 / Published: 29 August 2021
(This article belongs to the Section Molecular Cancer Biology)
MYC-driven deregulation of microRNAs represents a critical event in human malignancies, including multiple myeloma (MM). Although the introduction of new therapeutic strategies has prolonged survival of patients, MM remains an incurable disease, often due to the onset of drug resistance. MYC hyperactivation is involved in the development of resistance to immunomodulatory imide drugs (IMiDs), but the mechanism is still unclear. Here, we report that MYC represses the transcription of tumor suppressor miR-22 in MM, and that low miR-22 expression is associated with IMiD resistance in MM patients. By in silico and in vitro analysis, we show that miR-22 mimics affect MYC signaling, leading to MM cell death in MYC proficient cells. Furthermore, we demonstrate here that lenalidomide treatment enhances miR-22 activity by reducing the MYC inhibitory effect, and that the combination of lenalidomide with miR-22 mimics restores drug sensitivity, leading to synergistic anti-MM activity.
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 MMRF-CoMMpass 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. View Full-Text
Keywords: multiple myeloma; MYC; microRNA; miR-22; lenalidomide; NK cells multiple myeloma; MYC; microRNA; miR-22; lenalidomide; NK cells
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MDPI and ACS Style

Caracciolo, D.; Riillo, C.; Juli, G.; Scionti, F.; Todoerti, K.; Polerà, N.; Grillone, K.; Fiorillo, L.; Arbitrio, M.; Di Martino, M.T.; Neri, A.; Tagliaferri, P.; Tassone, P. miR-22 Modulates Lenalidomide Activity by Counteracting MYC Addiction in Multiple Myeloma. Cancers 2021, 13, 4365. https://doi.org/10.3390/cancers13174365

AMA Style

Caracciolo D, Riillo C, Juli G, Scionti F, Todoerti K, Polerà N, Grillone K, Fiorillo L, Arbitrio M, Di Martino MT, Neri A, Tagliaferri P, Tassone P. miR-22 Modulates Lenalidomide Activity by Counteracting MYC Addiction in Multiple Myeloma. Cancers. 2021; 13(17):4365. https://doi.org/10.3390/cancers13174365

Chicago/Turabian Style

Caracciolo, Daniele, Caterina Riillo, Giada Juli, Francesca Scionti, Katia Todoerti, Nicoletta Polerà, Katia Grillone, Lucia Fiorillo, Mariamena Arbitrio, Maria T. Di Martino, Antonino Neri, Pierosandro Tagliaferri, and Pierfrancesco Tassone. 2021. "miR-22 Modulates Lenalidomide Activity by Counteracting MYC Addiction in Multiple Myeloma" Cancers 13, no. 17: 4365. https://doi.org/10.3390/cancers13174365

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