STI571-resistant KT-1 cells are sensitive to interferon-α 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-α (IFN-α) on a novel STI571-resistant CML cell line and its molecular mechanisms in vitro. Materials and Methods. KT-1 is a unique CML cell line that remains sensitive to the therapeutic IFN-α 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-α than KT-1 cells. IFN-α 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-α–induced prolonged phosphorylation of Stat1 and recovered the sensitivity against IFN-α. These results indicated that the loss of TC-PTP is involved in the IFN-α–induced prolonged phosphorylation of Stat1 and in the higher sensitivity to IFN-α in KTR cells. Conclusion. We demonstrated that STI571-resistance does not confer cross-resistance to IFN-αin KT-1 cells. The loss of TC-PTP contributed to the IFN-α–induced prolonged phosphorylation of Stat1 and the higher sensitivity to IFN-α in KTR cells.