DNA methylation and globin gene expression in patients treated with 5-azacytidine.

T. J. Ley, N. P. Anagnou, C. T. Noguchi, A. N. Schechter, J. DeSimone, P. Heller, A. W. Nienhuis

Research output: Contribution to journalArticle

22 Scopus citations

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.

Original languageEnglish
Pages (from-to)457-474
Number of pages18
JournalProgress in Clinical and Biological Research
Volume134
StatePublished - Dec 1 1983
Externally publishedYes

Fingerprint Dive into the research topics of 'DNA methylation and globin gene expression in patients treated with 5-azacytidine.'. Together they form a unique fingerprint.

  • Cite this

    Ley, T. J., Anagnou, N. P., Noguchi, C. T., Schechter, A. N., DeSimone, J., Heller, P., & Nienhuis, A. W. (1983). DNA methylation and globin gene expression in patients treated with 5-azacytidine. Progress in Clinical and Biological Research, 134, 457-474.