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 therapeutic agents for a number of hematological malignancies, including chronic myelogenous leukemia (CML). Nevertheless, its efficacy is limited because of the development of resistance to IFN-alpha therapy. Previously, we established the novel human CML cell line KT-1, which is sensitive to the antiproliferative effects of IFN-alpha. Here, we report the establishment of an IFN-alpha-resistant subline, KT-1/A3R alpha 1000, by culturing KT-1/A3 cells (IFN-alpha-sensitive subline of KT-1) with increasing concentrations of IFN-alpha, in order to analyze the mechanism of acquisition of IFN-alpha resistance in CML cells after IFN-alpha therapy.


METHODS
We developed an IFN-alpha-resistant tumor cell variant, 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 ability to proliferate and its resistance to apoptosis in high concentrations of IFN-alpha. The induction of the ISGF3 complex in response to IFN-alpha alpha in KT-1/A3R alpha 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.


CONCLUSIONS
The KT-1/A3R alpha 1000 subline is a useful model for studying the mechanism of IFN-alpha resistance after IFN-alpha therapy.
Yamauchi
H
H
First Department of Internal Medicine, Ehime University School of Medicine.
Sakai
I
I
Narumi
H
H
Takeuchi
K
K
Soga
S
S
Fujita
S
S
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002461:Cell Line, Transformed / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism; D010766:Phosphorylation; D014443:Tyrosine / Q000378:metabolism
D000970:Antineoplastic Agents; D016898:Interferon-alpha; D014443:Tyrosine