title: STI571-resistant KT-1 cells are sensitive to interferon-alpha accompanied by the loss of T-cell protein tyrosine phosphatase and prolonged phosphorylation of Stat1.
abstract: OBJECTIVE
  The high incidence of acquired drug resistance to STI571 during treatment of chronic myelogenous leukemia (CML) patients in blast crisis has become a problem. We studied the effects of interferon-alpha (IFN-alpha) on a novel STI571-resistant CML cell line and its molecular mechanisms in vitro.
  
  
  METHODS
  KT-1 is a unique CML cell line that remains sensitive to the therapeutic IFN-alpha concentration. We developed novel STI571-resistant KT-1 cells (designated KTR cells) by gradually increasing the concentration of STI571.
  
  
  RESULTS
  All seven KTR clones became more sensitive to IFN-alpha than KT-1 cells. IFN-alpha induced more prolonged phosphorylation of Stat1 for 24 hours in all seven KTR clones than in KT-1cells. Tyrosine phosphorylation of Jak1 in KTR cells was not prolonged compared to KT-1cells. T-cell protein tyrosine phosphatase (TC-PTP) was down-regulated in all KTR clones, and SH-PTP1 phosphatase also was down-regulated in some KTR clones. The transient transduction of TC-PTP cDNA into the KTR subline prevented the IFN-alpha-induced prolonged phosphorylation of Stat1 and recovered the sensitivity against IFN-alpha. These results indicated that the loss of TC-PTP is involved in the IFN-alpha-induced prolonged phosphorylation of Stat1 and in the higher sensitivity to IFN-alpha in KTR cells.
  
  
  CONCLUSIONS
  We demonstrated that STI571-resistance does not confer cross-resistance to IFN-alphain KT-1 cells. The loss of TC-PTP contributed to the IFN-alpha-induced prolonged phosphorylation of Stat1 and the higher sensitivity to IFN-alpha in KTR cells.
authors.affiliation: Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Takatsune
authors.initials: T
authors.lastname: Shimizu
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Miyakawa
authors.forename: Atsushi
authors.initials: A
authors.lastname: Oda
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kizaki
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Ikeda
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001483:Base Sequence; D001549:Benzamides; D002460:Cell Line; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate; D017404:In Situ Hybridization, Fluorescence; D016898:Interferon-alpha / Q000494:pharmacology*; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*; D050794:STAT1 Transcription Factor; D013601:T-Lymphocytes / Q000187:drug effects* / Q000201:enzymology; D015534:Trans-Activators / Q000378:metabolism*; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D017931:DNA Primers; D004268:DNA-Binding Proteins; D016898:Interferon-alpha; D010879:Piperazines; D011743:Pyrimidines; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D000068877:Imatinib Mesylate; D017027:Protein Tyrosine Phosphatases