Development of interferon-alpha resistant subline from human chronic myelogenous leukemia cell line KT-1

Objective Interferon-alpha (IFN-alpha) is one of the most effective therape utic agents for a number of hematological malignancies, including chronic m yelogenous leukemia (CML). Nevertheless, its efficacy is limited because of the development of resistance to IFN-oc therapy. Previously, we establishe d the novel human CML cell line KT-1, which is sensitive to the antiprolife rative effects of IFN-alpha. Here, we report the establishment of an IFN-al pha -resistant subline, KT-1/A3R alpha 1000, by culturing KT-1/A3 cells (IF N-alpha -sensitive subline of KT-I) with increasing concentrations of IFN-a lpha, In order to analyze the mechanism of acquisition of IFN-alpha resista nce in CML cells after IFN-alpha therapy. Subjects and Methods We developed an IFN-alpha -resistant tumor cell varian t, KT-1/A3R alpha 1000, from the KT-1/A3 cell line by culturing cells with increasing concentrations of IFN-alpha. This subline was examined for its a bility to proliferate and its resistance to apoptosis in high concentration s of IFN-alpha. The induction of the ISGF3 complex in response to IFN-alpha in KT-1/A3Ra 1000 was compared with that in the parental cell. Results The levels of interferon-stimulated gene factor 3 components (STAT1 , STAT2, and p48) proteins and STAT2 tyrosine phosphorylation induced after IFN-alpha treatment were unchanged, but formation of the ISGF3 complex was remarkably reduced in KT-1/A3R alpha 1000 cells compared to parental cells . Conclusion The KT-1/A3R alpha 1000 subline is a useful model for studying t he mechanism of IFN-alpha resistance after IFN-alpha therapy.