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 syndrome and acute myeloid leukemia, but DAC‐resistance often occurs and leads to treatment failure. Therefore, elucidating the mechanisms of DAC resistance is 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‐resistant cell line (KG1a‐DAC) from its parental human leukemia‐derived cell line KG1a and observed that EVPs released from KG1a‐DAC can promote DAC‐resistant in KG1a cells. Moreover, treatment with KG1a‐DAC EVPs reduced the expression of cyclin‐dependent kinase inhibitor 2B (CDKN2B) in KG1a cells. miRNA‐Seq analysis 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.

Extracellular vesicles in hematological malignancies: EV-dence for reshaping the tumoral microenvironment

“…Resistance to decitabine, a commonplace front-line therapy for AML patients, is promoted by the transfer of miR-4755-5p within EVs from KG1a decitabine resistant cells to other KG1a cells (AML cell line). Following this transfer, CDKN2B, a cyclin dependent kinase inhibitor displays diminished expression indicating direct targeting by miR-4755-5p ( 66 ). Further highlighting the importance of sEV shedding in the AML ME, miR-34c-5p, a microRNA downregulated in AML, was described to induce leukemic stem cell (LSC) senescence and promote the eradication of LSCs ( 67 ).…”