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.
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.
Shimizu
Takatsune
T
Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
Miyakawa
Yoshitaka
Y
Oda
Atsushi
A
Kizaki
Masahiro
M
Ikeda
Yasuo
Y
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
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