{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T06:46:17Z","timestamp":1782369977894,"version":"3.54.5"},"reference-count":27,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2014,1,30]],"date-time":"2014-01-30T00:00:00Z","timestamp":1391040000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2014,3]]},"abstract":"<jats:p>This study found that long\u2010term exposure of chronic myelogenous leukemia (<jats:styled-content style=\"fixed-case\">CML<\/jats:styled-content>) <jats:styled-content style=\"fixed-case\">K<\/jats:styled-content>562 cells to <jats:styled-content style=\"fixed-case\">BCR<\/jats:styled-content>\/<jats:styled-content style=\"fixed-case\">ABL<\/jats:styled-content> thyrosine kinase inhibitors (<jats:styled-content style=\"fixed-case\">TKI<\/jats:styled-content>) caused drug\u2010resistance in association with an increase in levels of <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> methyltransferases (<jats:styled-content style=\"fixed-case\">DNMT<\/jats:styled-content>) and a decrease in levels of micro<jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content> miR\u2010217. These observations are clinically relevant; an increase in levels of <jats:styled-content style=\"fixed-case\">DNMT<\/jats:styled-content>3A in association with downregulation of miR\u2010217 were noted in leukemia cells isolated from individuals with <jats:styled-content style=\"fixed-case\">BCR<\/jats:styled-content>\/<jats:styled-content style=\"fixed-case\">ABL TKI<\/jats:styled-content>\u2010resistant Philadelphia chromosome positive acute lymphoblastic leukemia (Ph<jats:sup>+<\/jats:sup> <jats:styled-content style=\"fixed-case\">ALL<\/jats:styled-content>) and <jats:styled-content style=\"fixed-case\">CML<\/jats:styled-content>. Further studies with <jats:styled-content style=\"fixed-case\">TKI<\/jats:styled-content>\u2010resistant K562 cells found that forced expression of miR\u2010217 inhibited expression of <jats:styled-content style=\"fixed-case\">DNMT<\/jats:styled-content>3A through a miR\u2010217\u2010binding site within the 3\u2032\u2010untranslated region of <jats:styled-content style=\"fixed-case\">DNMT<\/jats:styled-content>3A and sensitized these cells to growth inhibition mediated by the <jats:styled-content style=\"fixed-case\">TKI<\/jats:styled-content>. Of note, long\u2010term exposure of K562 cells to dasatinib (10\u00a0nM) together with 5\u2010Aza\u20102\u2032\u2010deoxycytidine (5\u2010AzadC) (0.1\u00a0\u03bcM) potently inhibited proliferation of these cells in association with upregulation of miR\u2010217 and downregulation of <jats:styled-content style=\"fixed-case\">DNMT<\/jats:styled-content>3A <jats:italic>in vitro<\/jats:italic>. In addition, a decrease in levels of <jats:styled-content style=\"fixed-case\">DNMT<\/jats:styled-content>3A and an increase in levels of miR\u2010217 were noted in K562 tumors growing in immune\u2010deficient mice that were treated with the combination of 5\u2010AzadC and dasatinib. Taken together, Ph<jats:sup>+<\/jats:sup> leukemia cells acquire <jats:styled-content style=\"fixed-case\">TKI<\/jats:styled-content> resistance via downregulation of miR\u2010217 and upregulation of <jats:styled-content style=\"fixed-case\">DNMT<\/jats:styled-content>3A. Inhibition of <jats:styled-content style=\"fixed-case\">DNMT<\/jats:styled-content>3A by forced expression of miR\u2010217 or 5\u2010<jats:styled-content style=\"fixed-case\">A<\/jats:styled-content>zad<jats:styled-content style=\"fixed-case\">C<\/jats:styled-content> may be useful to prevent drug resistance in individuals who receive <jats:styled-content style=\"fixed-case\">TKI<\/jats:styled-content>.<\/jats:p>","DOI":"10.1111\/cas.12339","type":"journal-article","created":{"date-parts":[[2013,12,18]],"date-time":"2013-12-18T18:43:47Z","timestamp":1387392227000},"page":"297-307","source":"Crossref","is-referenced-by-count":52,"title":["Downregulation of miR\u2010217 correlates with resistance of ph<sup>+<\/sup> leukemia cells to <scp>ABL<\/scp> tyrosine kinase inhibitors"],"prefix":"10.1111","volume":"105","author":[{"given":"Chie","family":"Nishioka","sequence":"first","affiliation":[{"name":"Department of Hematology and Respiratory Medicine Kochi Medical School Kochi University 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