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  • Title: DNA methylation and globin gene expression in patients treated with 5-azacytidine.
    Author: Ley TJ, Anagnou NP, Noguchi CT, Schechter AN, DeSimone J, Heller P, Nienhuis AW.
    Journal: Prog Clin Biol Res; 1983; 134():457-74. PubMed ID: 6198660.
    Abstract:
    5-Azacytidine, a cytidine analog, stimulated fetal hemoglobin synthesis in five patients who had either severe beta-thalassemia or sickle cell anemia. After treatment, a reduction in the frequency of methylated cytosine residues was observed at all Hpa II sites examined. Despite causing "global" hypomethylation, 5-azacytidine augmented the synthesis of gamma-globin only. Although gamma-gene hypomethylation and increased gamma-gene expression seem to be linked, hypomethylation near other genes was not sufficient to activate transcription. These data suggest that the gamma genes lie in a unique "preactivational" state responsive to hypomethylation, and that other genes are repressed in bone marrow cells by different mechanisms. DNA hypomethylation and an increased concentration of gamma-mRNA were observed in bone marrow cells 2 days after initiation of treatment, indicating that 5-azacytidine may act directly on differentiated erythroid precursors. This compound probably affects early erythroid progenitors as well, since an increased level of gamma-globin synthesis persists for 1-2 weeks after the drug is stopped. A direct effect on erythroid progenitors was also suggested by in vitro assays: Erythroid colonies derived from progenitor cells obtained on day 2 of treatment produced more Hb F than colonies derived from progenitors obtained before 5-azacytidine was given.
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