Transfer of miR-4755-5p through extracellular vesicles and particles induces decitabine resistance in recipient cells by targeting CDKN2B.

Abstract

Decitabine (5-aza-2-deoxycytidine, DAC),a DNA-hypomethylating agent, has been one of the frontline therapies for clonal hematopoietic stem cell disorders, such as myelodysplastic syndromeand acute myeloid leukemia,but DAC-resistance often occurs and leads to treatment failure. Therefore, elucidating the mechanisms of DAC resistanceis important for improving its therapeutic efficacy. The extracellular vesicles and particles (EVPs) have been reported to be involved in mediating drug resistance by transporting diverse bioactive components. In this study, we established the DAC-resistantcell line (KG1a-DAC)from its parental human leukemia-derived cell line KG1a and observed that EVPs released from KG1a-DACcan promote DAC-resistant in KG1a cells. Moreover, treatment with KG1a-DACEVPs reduced the expression of cyclin-dependent kinase inhibitor 2B (CDKN2B)in KG1a cells. miRNA-Seqanalysis revealed that miR-4755-5p is overexpressed in EVPs from KG1a-DAC. Dual-luciferase reporter assay and flow cytometry analysis confirmed that miR-4755-5p rendered KG1a cells resistant to the DAC by targeting CDKN2B gene. Taken together, miR-4755-5p in EVPs released from the DAC-resistant cells plays an essential role in inducing DAC-resistance, and is a potential therapeutic target for suppression of DAC resistance.