Imatinib (IM) is a first-line therapeutic drug for chronic myeloid leukemia (CML), a hematological disease. Mutations in the BCR-ABL domain increase formation of IM resistance in CML. However, not all patients are BCR-ABL domain-mutant dependent. Investigating non-mutant mechanisms in the development of acquired IM resistance is a critical issue. We explored the mechanisms which influence IM efficacy and resistance in CML. Higher protective autophagy was identified in IM-resistant K562 (K562R) cells. Inhibition of autophagy by the inhibitors, chloroquine and 3-methyladenine, enhanced IM's efficacy in K562R cells. In addition, microRNA (miR)-199a/b-5p were downregulated in K562R cells compared to parent cells. Overexpression of miR-199a/b-5p reduced autophagy and induced cell apoptosis, resulting in enhanced IM's efficacy in K562R cells. Moreover, expression levels of the Wingless-type MMTV integration site family member 2 (WNT2), a positive regulator of autophagy, were significantly higher in K562R cells, and it was validated as a direct target gene of miR-199a/b-5p. Overexpressions of miR-199a/b-5p inhibited WNT2 downstream signaling. Furthermore, overexpression and knockdown of WNT2 influenced autophagy formation and CML drug sensitivity to IM. Overexpression of WNT2 could also reverse miR-199a/b-5p-enhanced IM efficacy in K562R cells. These results emphasized that miR-199a/b-5p inhibited autophagy via repressing WNT2 signaling and might provide novel therapeutic strategies for future IM-resistant CML therapy and drug development.
- Chronic myeloid leukemia (CML)
- Imatinib resistance
ASJC Scopus subject areas