Resistance to Interferon-α in a Mouse B-Cell Lymphoma Involves DNA Methylation

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Abstract
Resistance to interferon-α (IFN-α) in the 38C13 B-lymphoma cell line results in the loss of antiviral, antiproliferative, and immune regulatory functions of IFN-α. Mutagenesis with ethylmethylsulfonic acid (EMS), which can induce point mutations in DNA, increases the frequency of resistance to IFN-α 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-α–resistant cells to the IFN-α–sensitive state. Resistance to IFN-α occurs spontaneously at a rate of approximately 3 × 10−6 variants/cell · generation, and is stable for more than 30 passages without selection in IFN-α. There is no evidence that gene amplification contributes to the high rate of resistance to IFN-α in these cells. These results indicate that DNA mutation and methylation are important in the development of IFN-α resistance in these cells.

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