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

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 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.

Exploiting DNA Ligase III addiction of multiple myeloma by flavonoid Rhamnetin

“…We demonstrated the activity of MYC as a promoter of LIG3 mRNA expression and, therefore, as a master regulator of Alt-NHEJ in MM. This finding is in line with our data reporting resistance to RHM in U266 cells which are indeed MYC defective [67] and with other previous observations that highlighted a higher mutational load in relapsed refractory MM (RRMM) and a crucial role exerted by MYC expression as a predictive factor to DDR inhibitors response, [68][69][70], further confirming that Alt-NHEJ function may be more complex than a simple back-up system. Although further investigation is required to finally validate the specific binding site on LIG3 and dissect the mechanisms of anti-tumor activity, and integrative multi-omics platforms at different molecular levels might provide valuable insights into the complexity of this biological system [71][72][73][74][75][76][77], based on our findings, we could hypothesize that RHM impairs DNA Ligase III activity by binding to PCG of DBD, thus hampering DNA damage recognition, repair and chromosome translocations (Fig.…”

“…We demonstrated the activity of MYC as a promoter of LIG3 mRNA expression and, therefore, as a master regulator of Alt-NHEJ in MM. This finding is in line with our data reporting resistance to RHM in U266 cells which are indeed MYC defective [ 67 ] and with other previous observations that highlighted a higher mutational load in relapsed refractory MM (RRMM) and a crucial role exerted by MYC expression as a predictive factor to DDR inhibitors response, [ 68 – 70 ], further confirming that Alt-NHEJ function may be more complex than a simple back-up system.…”

Exosomal miRNAs in the Tumor Microenvironment of Multiple Myeloma

“…Interestingly, the non-exosomal source (intracellular) of miR-22 exerted anti-drug resistance effects in breast cancer cells, improved radiosensitivity in these cells by targeting Sirt1, and suppressed tumorigenesis [ 113 ]. In MM cells, intracellular miR-22 improved the response to immunomodulatory imide drugs (IMiDs) by targeting MYC addiction in MM cells [ 114 ]. MYC has a major role in the development of resistance to anti-MM drugs and the progression of the disease by the regulation of the miRNAs [ 114 ].…”

“…In MM cells, intracellular miR-22 improved the response to immunomodulatory imide drugs (IMiDs) by targeting MYC addiction in MM cells [ 114 ]. MYC has a major role in the development of resistance to anti-MM drugs and the progression of the disease by the regulation of the miRNAs [ 114 ]. On the other hand, intracellular miR-22 in MM cells targets the LIG3 protein, which leads to increased DNA damage and death in MM cells.…”

The New Microtubule-Targeting Agent SIX2G Induces Immunogenic Cell Death in Multiple Myeloma

“…Multiple Myeloma (MM) is a plasma cell malignancy characterized by the accumulation of tumor cells in the bone marrow (BM) by the secretion of a monoclonal immunoglobulin also named M-protein and by multi-organ damage [ 24 ]. The high genetic heterogeneity and the crucial role of the BM milieu (BMM) remarkably limit the efficacy of available therapeutics [ 25 , 26 , 27 , 28 ]. The introduction of immunomodulatory drugs, such as thalidomide or lenalidomide, and proteasome inhibitors such as bortezomib and carfilzomib, has improved patients’ clinical outcome [ 24 , 29 ].…”