Downregulation of miR-217 correlates with resistance of Ph(+) leukemia cells to ABL tyrosine kinase inhibitors.
Bottom Line: This study found that long-term exposure of chronic myelogenous leukemia (CML) K562 cells to BCR/ABL thyrosine kinase inhibitors (TKI) caused drug-resistance in association with an increase in levels of DNA methyltransferases (DNMT) and a decrease in levels of microRNA miR-217.Further studies with TKI-resistant K562 cells found that forced expression of miR-217 inhibited expression of DNMT3A through a miR-217-binding site within the 3'-untranslated region of DNMT3A and sensitized these cells to growth inhibition mediated by the TKI.In addition, a decrease in levels of DNMT3A and an increase in levels of miR-217 were noted in K562 tumors growing in immune-deficient mice that were treated with the combination of 5-AzadC and dasatinib.
Affiliation: Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Japan.Show MeSH
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Mentions: We next examined whether DNMT inhibitor 5-AzadC prevented resistance to dasatinib in K562 cells. K562 cells were cultured with either dasatinib (10 nM, 96 h – 2 months) and/or 5-AzadC (0.1 μM, 96 h – 2 months). The culture media were replaced and drugs were added every 5 days. 5-AzadC only slightly inhibited the proliferation of K562 cells. K562 cells lost their sensitivity to dasatinib after 2 months culture in the presence of dasatinib (Fig.3a). Notably, when K562 cells were cultured with a combination of dasatinib (10 nM) and 5-AzadC (0.1 μM), their proliferation was potently inhibited even after 2 months in parallel with upregulation of miR-29b-1, miR-29b-2 and miR-217 and downregulation of DNMT (Fig.3b,c).
Affiliation: Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Japan.