When cells are treated with interferon several new proteins are induced. We have isolated by differential screening two cDNA clones corresponding to human genes inducible by IFN-alpha, termed IFI-4 and IFI-54K. The accumulation of the corresponding mRNA was followed as a function of either IFN dose or of time. The IFI-4 and IFI-54K genes, as well as two previously isolated IFN-inducible genes, namely the IFI-56K and low-molecular-weight 2-5A synthetase, were localized on the human chromosomes. Using cloned probes on Southern blots of DNA from a panel of rodent-human somatic cell hybrids, we have assigned the IFI-4 gene to chromosome 1 and the gene coding for the low-molecular-weight 2-5A synthetase to chromosome 12. We also showed that the IFI-54K and IFI-56K genes, unlike most of the IFN-inducible genes, are syntenic. They are both located on chromosome 10. In addition, evidence is given for the presence of a pseudogene homologous to IFI-56K on chromosome 13.
Recombinant human interferon-alpha (IFN-alpha) can induce a hematologic remission in patients with chronic myeloid leukemia. However, some patients are resistant and others develop late resistance to the IFN- alpha treatment. To understand the molecular mechanism of this resistance, we have analyzed the expression of 10 IFN-inducible genes in the cells of three resistant patients, two responsive patients, and six healthy controls. Northern blot hybridizations showed that all the genes were induced in in vitro IFN-alpha treated peripheral blood cells of the patients and healthy controls. These genes were also inducible in peripheral blood and bone marrow cells of two out of two resistant patients administered an injection of IFN-alpha. We conclude that the resistance to the IFN-alpha treatment of the chronic myeloid leukemia patients we studied is not due to (1) the absence of induction of any of the 10 IFN-inducible genes we studied, including the low-molecular- weight 2′-5′oligoadenylate synthetase; (2) the presence of an antagonist of IFN-alpha in the peripheral blood or bone marrow cells; and (3) the presence of neutralizing anti-IFN-alpha antibodies.
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