ciRS‐7 circular RNA overexpression in plasma cells is a promising molecular biomarker of unfavorable prognosis in multiple myeloma

• Published in: EJHaem 2024-08, Vol.5 (4), p.677-689
• Main Authors: Papatsirou, Maria, Kontos, Christos K., Ntanasis‐Stathopoulos, Ioannis, Malandrakis, Panagiotis, Theodorakakou, Foteini, Liacos, Christine‐Ivy, Mavrianou‐Koutsoukou, Nefeli, Fotiou, Despina, Migkou, Magdalini, Gavriatopoulou, Maria, Kastritis, Efstathios, Dimopoulos, Meletios A., Scorilas, Andreas, Terpos, Evangelos
• Format: Article
• Language: English
• Subjects: Benign monoclonal gammopathy; Binding sites; Biomarkers; Bone marrow; Cancer; CDR1‐AS; circRNA; Circular RNA; Complementarity-determining region 1; Genomes; Immunomodulation; Medical prognosis; microRNA; MicroRNAs; miRNA; molecular biomarker; Multiple myeloma; non‐coding RNA; Plasma; plasma cell dyscrasia; Plasma cells; Prognosis; Ribonucleic acid; RNA; Tumors
• ISSN: 2688-6146; 2688-6146
• DOI: 10.1002/jha2.903

Several non‐coding RNAs are known to be associated with the pathobiology and progression of multiple myeloma (MM). ciRS‐7 (also known as CDR1‐AS), a key oncogenic circular RNA (circRNA) that sponges miR‐7‐5p and other cancer‐related microRNAs, was recently found to be downregulated in malignant plasma cells resistant to immunomodulatory drugs. Considering that various circRNAs have a strong potential as molecular biomarkers, we aimed to investigate the expression of ciRS‐7 in plasma cell disorders, assess its prognostic importance in MM, and compare these findings with those of individuals with smoldering MM (SMM) and monoclonal gammopathy of unknown significance (MGUS). This study included 171 patients (110 newly diagnosed MM, 34 SMM, and 27 MGUS cases), from which bone marrow aspirate samples were collected for CD138+ plasma cell selection. Total RNA was reversely transcribed using random hexamer primers, and the expression levels of ciRS‐7 were quantified using an in‐house‐developed protocol that includes pre‐amplification and real‐time quantitative polymerase chain reaction. ciRS‐7 levels were found to significantly differ among CD138+ plasma cells of MM, SMM, and MGUS patients. ROC analysis indicated that ciRS‐7 expression effectively distinguishes between MM and SMM patients. Moreover, high levels of ciRS‐7 were associated with unfavorable prognosis in MM, independently of MM patients’ age and Revised International Staging System stage. Additionally, in silico analysis predicted the binding of 85 microRNAs to ciRS‐7. In conclusion, this study provides novel insights into the role of ciRS‐7 as a promising molecular marker able to distinguish MM from SMM and predict prognosis in MM. Considering that various circular RNAs (circRNAs) have a strong potential as molecular biomarkers and that ciRS‐7 has previously been shown to be downregulated in multiple myeloma (MM) patients having developed tolerance to immunomodulatory drugs, we aimed to investigate the expression of this circRNA in plasma cell disorders, assess its prognostic importance in MM, and compare these findings with those of individuals with smoldering multiple myeloma (SMM) and monoclonal gammopathy of unknown significance (MGUS). ciRS‐7 expression in plasma cells differs between MGUS, SMM, and MM patients, and can distinguish MM from SMM, while elevated ciRS‐7 expression predicts an unfavorable prognosis in MM, independently of patients' age and R‐ISS stage.