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Downregulation of miR-217 correlates with resistance of ph+ leukemia cells to ABL tyrosine kinase inhibitors

C. Nishioka,T. Ikezoe,Jing Yang,Atsuya Nobumoto,Masayuki Tsuda,A. Yokoyama

Published 2014 in Cancer Science

ABSTRACT

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. These observations are clinically relevant; an increase in levels of DNMT3A in association with downregulation of miR‐217 were noted in leukemia cells isolated from individuals with BCR/ABL TKI‐resistant Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) and CML. 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. Of note, long‐term exposure of K562 cells to dasatinib (10 nM) together with 5‐Aza‐2′‐deoxycytidine (5‐AzadC) (0.1 μM) potently inhibited proliferation of these cells in association with upregulation of miR‐217 and downregulation of DNMT3A in vitro. 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. Taken together, Ph+ leukemia cells acquire TKI resistance via downregulation of miR‐217 and upregulation of DNMT3A. Inhibition of DNMT3A by forced expression of miR‐217 or 5‐AzadC may be useful to prevent drug resistance in individuals who receive TKI.

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