title: Downregulation of miR-217 correlates with resistance of Ph(+) leukemia cells to ABL tyrosine kinase inhibitors.
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.
authors.affiliation: Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Japan.
authors.forename: Chie
authors.initials: C
authors.lastname: Nishioka
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ikezoe
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Atsuya
authors.initials: A
authors.lastname: Nobumoto
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tsuda
authors.forename: Akihito
authors.initials: A
authors.lastname: Yokoyama
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D000069439:Dasatinib; D000077209:Decitabine; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D005260:Female; D015870:Gene Expression; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D010677:Philadelphia Chromosome; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; C553315:MIRN217 microRNA, human; D035683:MicroRNAs; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000077209:Decitabine; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; C498826:nilotinib; D001374:Azacitidine; D000069439:Dasatinib
keywords: 5-AzadC; DNA methyltransferases; chronic myelogenous leukemia; dasatinib; miR-217