Potential role of exosome-associated microRNA panels and in vivo environment to predict drug resistance for patients with multiple myeloma

Abstract

Multiple myeloma (MM) is the second most common hematologic neoplasms and an appropriate in vivo environment for myeloma cells has potential implications for initiation, progression, and metastasis of MM. Exosomes, entities carrying microRNAs (miRNAs) to target locations, participate in the cross-talk between myeloma cells and nonmalignant components of the in vivo environment. This study disclosed the emerging roles of circulating exosome-associated miRNAs in drug resistance (DR) of MM. To this end, the medical records of consecutively hospitalized MM patients, who received novel agents-based therapies, were analyzed. Then, an optimized procedure was established for exosome isolation and exosomal RNA analysis. The exosome-associated miRNA expression patterns for predicting bortezomib (Bz) resistance of MM were further examined using a microarray. In total, 204 patients were enrolled with DR rates of 36.5%, 73.1% and 81.8% in the bortezomib (Bz), thalidomide and lenalidomide containing groups. The serum total light chain ratio ≥ 100, CRP ≥ 20 mg/L, and the second-line usage increased risks of acquired Bz-resistance. Among 68 cases having genetic tests, a high risk factor for predicting de novo DR was 1q21 amplification, which also correlated with lower levels of cholesterol and LDL-C. Moreover, nano-sized exosomes were isolated with significantly increasing internal RNAs and down-regulation of exosomal miR-16-5p, miR-15a-5p and miR-20a-5p, miR-17-5p was revealed in the patients resistant to Bz. The routine workup of MM hardly suggested a value for DR prediction. The circulating exosomes carrying miRNAs provided a window that permits a better understanding of the in vivo intercellular crosstalk in MM patients.

PIWI-Interacting RNA-004800 Is Regulated by S1P Receptor Signaling Pathway to Keep Myeloma Cell Survival

“…Exosomes from bone marrow supernatant were obtained by using the Total Exosome Isolation Kit (from plasma) (Invitrogen, Carlsbad, CA, USA). Exosomes from the cell culture supernatant were obtained as reported (14). Nanoparticle tracking analysis (NTA) at VivaCell Biosciences with ZetaView PMX 110 (Particle Metrix, Meerbusch, Germany) was used to measure the exosome particle size and concentration.…”

Vesicle-MaNiA: extracellular vesicles in liquid biopsy and cancer

“…miRs are small double-stranded RNAs with strong regulatory potential [44] and its differential abundance in cancer-derived EVs have been associated with the presence and aggressiveness of squamous cell carcinoma, prostate and bladder cancer, among others [22, 30, 34–36, 45–55]…”

MicroRNAs and exosomes: Small molecules with big actions in multiple myeloma pathogenesis

“…Circulating exosome‐related miRNAs were recently utilized as prognostic biomarkers to predict acquired or primary drug resistance, by comparing responsive and bortezomib‐resistant patients with MM. In fact, down‐regulation of four exosomal miRNAs, including miR‐17‐5p, miR‐20a‐5p, miR‐15a‐5p, and miR‐16‐5p were observed in the bortezomib‐resistant patients . As discussed before, miRNAs are implicated in bone metabolism and MM‐bone disease.…”

“…In fact, down-regulation of four exosomal miRNAs, including miR-17-5p, miR-20a-5p, miR-15a-5p, and miR-16-5p were observed in the bortezomib-resistant patients. 98 As discussed before, miRNAs are implicated in bone metabolism and MM-bone disease. Recently, Sun et al showed that exosomal miR-214 secreted by OCs is transferred into OBs, by EphA2/EphrinA2 molecules, through suppressing their activities.…”