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

作者：Nishioka Chie; Ikezoe Takayuki^*; Yang Jing; Nobumoto Atsuya; Tsuda Masayuki; Yokoyama Akihito

来源：CANCER SCIENCE, 2014, 105(3): 297-307.

DOI：10.1111/cas.12339

• 5-AzadC
• chronic myelogenous leukemia
• dasatinib
• DNA methyltransferases
• miR-217

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 (10nM) together with 5-Aza-2-deoxycytidine (5-AzadC) (0.1M) 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.

• 出版日期2014-3