Open AccessDownregulation of miR‐217 correlates with resistance of ph + leukemia cells to ABL tyrosine kinase inhibitors
Author(s) -
Nishioka Chie,
Ikezoe Takayuki,
Yang Jing,
Nobumoto Atsuya,
Tsuda Masayuki,
Yokoyama Akihito
Publication year - 2014
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.12339
Subject(s) - downregulation and upregulation , dasatinib , k562 cells , chronic myelogenous leukemia , cancer research , leukemia , abl , tyrosine kinase , imatinib , biology , immunology , myeloid leukemia , microbiology and biotechnology , signal transduction , biochemistry , gene
This study found that long‐term exposure of chronic myelogenous leukemia ( CML ) K 562 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 micro RNA miR‐217. These observations are clinically relevant; an increase in levels of DNMT 3A 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 DNMT 3A through a miR‐217‐binding site within the 3′‐untranslated region of DNMT 3A 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 DNMT 3A in vitro . In addition, a decrease in levels of DNMT 3A 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 DNMT 3A. Inhibition of DNMT 3A by forced expression of miR‐217 or 5‐ A zad C may be useful to prevent drug resistance in individuals who receive TKI .