title: Resistance to interferon-alpha in a mouse B-cell lymphoma involves DNA methylation.
abstract: Resistance to interferon-alpha (IFN-alpha) in the 38C13 B-lymphoma cell line results in the loss of antiviral, antiproliferative, and immune regulatory functions of IFN-alpha. Mutagenesis with ethylmethylsulfonic acid (EMS), which can induce point mutations in DNA, increases the frequency of resistance to IFN-alpha 20 to 40-fold. In contrast, treatment with 5-azacytidine, which causes hypomethylation of DNA, reduces the frequency of resistance to 5-10% of control. Furthermore, 5-azacytidine treatment reverts IFN-alpha-resistant cells to the IFN-alpha-sensitive state. Resistance to IFN-alpha occurs spontaneously at a rate of approximately 3 x 10(-6) variants/cell.generation, and is stable for more than 30 passages without selection in IFN-alpha. There is no evidence that gene amplification contributes to the high rate of resistance to IFN-alpha in these cells. These results indicate that DNA mutation and methylation are important in the development of IFN-alpha resistance in these cells.
authors.affiliation: Department of Medicine, Stanford University School of Medicine, CA 94305.
authors.forename: T R
authors.initials: TR
authors.lastname: Reid
authors.forename: T C
authors.initials: TC
authors.lastname: Merigan
authors.forename: T Y
authors.initials: TY
authors.lastname: Basham
mesh_terms: D000818:Animals; D001374:Azacitidine / Q000633:toxicity; D004247:DNA / Q000235:genetics / Q000378:metabolism*; D004351:Drug Resistance / Q000235:genetics; D005020:Ethyl Methanesulfonate / Q000633:toxicity; D016898:Interferon-alpha / Q000494:pharmacology*; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000378:metabolism*; D008745:Methylation; D051379:Mice; D016296:Mutagenesis / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: D016898:Interferon-alpha; D004247:DNA; D005020:Ethyl Methanesulfonate; D001374:Azacitidine