MiR-221 Sensitizes Chronic Myeloid Leukemia Cells to Imatinib By Targeting STAT5

Abstract

Imatinib, a tyrosine-kinase inhibitors (TKIs), is the first-line treatment in the early chronic phase of chronic myeloid leukemia (CML). In the last decade, the survival of patients with CML has significantly increased with the use of TKIs. However, the drug resistance is one major barrier in CML treatment. At present, although the research on CML TKIs resistance mechanism has made great progress, the underlying mechanism is complex and still not fully elucidated, especially the lack of understanding of the upstream common mechanism. MicroRNAs (miRNAs) are involved in various processes from the development to drug resistance of tumors, including chronic myeloid leukemia (CML). In this work, we examined the STAT5-related miRNA-expression profile in CML cell lines (K562 and imatinib-resistant K562/G) by quantitative real-time reverse-transcriptase polymerase chain reactions. MiR-221 expression was markedly decreased in K562/G cells and peripheral blood mononuclear cells from patients with treatment failure, when compared to K562 cells and patients with optimal responses respectively. We also observed the expression of STAT5 expression inversely correlated with miR-221 expression in CML cells. Additionally, STAT5 was validated in this study as a direct target of miR-221 in dual-luciferase reporter vector assays. MiR-221 restoration and STAT5 knockdown in K562/G cells increased the sensitivity of CML cells to imatinib by reducing the Bcl2: Bax ratio. Collectively, our data suggest that miR-221-STAT5 axis played crucial roles in controlling the sensitivity of CML cells to imatinib. DisclosuresNo relevant conflicts of interest to declare.