MicroRNA's in Multiple Myeloma: Drivers of Drug Resistance and Therapeutic Targets

Background and Objectives Multiple myeloma (MM) is a fatal malignancy characterized by the uncontrolled proliferation of mutated plasma cells within the bone marrow. It predominantly affects older adults and is associated with widespread tumor dissemination and diverse chromosomal abnormalities, which complicate treatment efforts. The heterogeneity and diverse mutations within MM contribute to inconsistent responses to chemotherapy and the development of drug resistance, impeding successful treatment outcomes. Materials and Methods We conducted a comprehensive review of literature from PubMed, Google Scholar, Clinical Trials databases, and other relevant sources. We analyzed key articles to extract necessary information on MM treatment and pathogenesis, from conception to August ۲۰۲۴. Results Proteasome inhibitors, immunomodulators, and monoclonal antibodies have significantly improved patient outcomes and survival rates in MM while maintaining manageable side effects. However, despite these advancements, MM remains incurable, with frequent relapses. A deeper understanding of MM's progression—from precursor to terminal stages—can reveal mechanisms underlying mutations, drug resistance, immune evasion, and relapse, which may serve as potential therapeutic targets. The treatment landscape for MM has evolved, with standard regimens including immunomodulators, proteasome inhibitors, monoclonal antibodies, and histone deacetylase inhibitors. Chemotherapy protocols vary; younger patients typically receive a combination of bortezomib, lenalidomide, and dexamethasone, while elderly, transplant-ineligible patients benefit more from the combination of bortezomib, melphalan, prednisone, and daratumumab. Despite these therapies, drug resistance remains a significant obstacle, limiting treatment efficacy and reducing overall survival. Recent research has shifted focus to epigenetic mechanisms, such as DNA methylation, histone modifications, and non-coding RNAs, particularly microRNAs (miRNAs), as key contributors to cancer development, including MM. Although chromosomal and gene mutations are established drivers of MM, miRNA dysregulation is increasingly recognized as a significant factor in MM pathogenesis and may serve as a diagnostic and prognostic biomarker. miRNAs, which are small non-coding RNA molecules, play diverse roles in MM, with emerging therapeutic strategies focusing on miRNA replacement or inhibition. Chemotherapy resistance in MM remains a critical issue, and miRNAs contribute to this phenomenon. For example, overexpression of miR-۲۲۱/۲۲۲ induces dexamethasone resistance by reducing autophagy via effects on ATG۱۲ and the p۲۷-mTOR pathway. Circular RNA-mediated miR-۱۲۹-۵p upregulation promotes bortezomib resistance, while miR-۱۵۵ influences dexamethasone resistance through the CD۴۷/TNFAIP۸ axis. In vitro studies show that miR-۲۹b induces apoptosis by suppressing the anti-apoptotic gene MCL۱ in MM cell lines. Numerous other miRNAs also play a role in chemoresistance in MM. Conclusion: The expanding understanding of miRNAs in MM pathogenesis, progression, and prognosis has opened up new therapeutic possibilities, particularly in combination with anti-myeloma drugs. However, drug resistance remains a major challenge. Current research is focused on elucidating miRNA-mediated mechanisms behind treatment resistance, although this area is still in its infancy.

کلیدواژه ها:

Multiple myeloma ، miRNA ، Drug Resistant ، Chemotherapy