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. MATERIALS AND 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. CONCLUSION: 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.
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. MATERIALS AND 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. CONCLUSION: 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: Krista M Heinonen; Nadia Dubé; Annie Bourdeau; Wayne S Lapp; Michel L Tremblay Journal: Proc Natl Acad Sci U S A Date: 2006-02-13 Impact factor: 11.205
Authors: Samia B Bachmann; Sandra C Frommel; Rosalba Camicia; Hans C Winkler; Raffaella Santoro; Paul O Hassa Journal: Mol Cancer Date: 2014-05-27 Impact factor: 27.401