title: Activation of STAT5 confers imatinib resistance on leukemic cells through the transcription of TERT and MDR1.
abstract: We used two imatinib resistant cell lines, K562-ADM cells, which over-express P-glycoprotein (a product of the ABCB1 gene, more commonly known as MDR1), and K562-hTERT cells, which over-express the telomerase reverse transcriptase (TERT), as models to show that the acquisition of multidrug resistance in CML is associated with the enhanced phosphorylation of signal transducer and activator of transcription 5 (STAT5). The induction of P-glycoprotein expression that occurred in response to adriamycin treatment was accompanied by increased phosphorylation of BCR-ABL and STAT5, as well as increased telomerase protein expression. Intriguingly, a ChIP assay using an anti-STAT5 antibody revealed direct binding of STAT5 to the promoter regions of both the human TERT gene and the MDR1 gene in K562-ADM cells. Conversely, silencing of endogenous STAT5 expression by siRNA significantly reduced both the expression of P-glycoprotein and telomerase activity and resulted in the recovery of the imatinib sensitivity of K562-ADM cells. These findings indicate a critical role for STAT5 in the induction of P-glycoprotein and in the modulation of telomerase activity in drug-resistant CML cells. Furthermore, primary leukemic cells obtained from patients in blast crisis showed increased levels of phospho-STAT5, P-glycoprotein and telomerase. In contrast, none of these proteins were detectable in the cells obtained from patients in the chronic phase. Together, these findings indicate a novel mechanism that contributes toward multidrug resistance involving STAT5 as a sensor for cytotoxic drugs in CML patients.
authors.affiliation: Department of Hematology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, Japan. yamadao@lab.twmu.ac.jp
authors.forename: Osamu
authors.initials: O
authors.lastname: Yamada
authors.forename: Kohji
authors.initials: K
authors.lastname: Ozaki
authors.forename: Thoru
authors.initials: T
authors.lastname: Furukawa
authors.forename: Mitsuyo
authors.initials: M
authors.lastname: Machida
authors.forename: Yan-Hua
authors.initials: YH
authors.lastname: Wang
authors.forename: Toshiko
authors.initials: T
authors.lastname: Motoji
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Mitsuishi
authors.forename: Masaharu
authors.initials: M
authors.lastname: Akiyama
authors.forename: Hisashi
authors.initials: H
authors.lastname: Yamada
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Kawauchi
authors.forename: Rumiko
authors.initials: R
authors.lastname: Matsuoka
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001549:Benzamides; D001752:Blast Crisis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D000068877:Imatinib Mesylate; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D001549:Benzamides; D047908:Intracellular Signaling Peptides and Proteins; D010879:Piperazines; D011743:Pyrimidines; D050799:STAT5 Transcription Factor; D004317:Doxorubicin; D000068877:Imatinib Mesylate; C509186:TERT protein, human; D019098:Telomerase