Azacytidine Causes Complex DNA Methylation Responses in Myeloid Leukemia

Mol Cancer Ther. 2008 Sep;7(9):2998-3005. doi: 10.1158/1535-7163.MCT-08-0411.

Abstract

Aberrant DNA methylation patterns play an important role in the pathogenesis of hematologic malignancies. The DNA methyltransferase inhibitors azacytidine and decitabine have shown significant clinical benefits in the treatment of myelodysplastic syndrome (MDS), but their precise mode of action remains to be established. Both drugs have been shown the ability to deplete DNA methyltransferase enzymes and to induce DNA demethylation and epigenetic reprogramming in vitro. However, drug-induced methylation changes have remained poorly characterized in patients and therapy-related models. We have now analyzed azacytidine-induced demethylation responses in myeloid leukemia cell lines. These cells showed remarkable differences in the drug-induced depletion of DNA methyltransferases that coincided with their demethylation responses. In agreement with these data, DNA methylation analysis of blood and bone marrow samples from MDS patients undergoing azacytidine therapy also revealed substantial differences in the epigenetic responses of individual patients. Significant, transient demethylation could be observed in 3 of 6 patients and affected many hypermethylated loci in a complex pattern. Our results provide important proof-of-mechanism data for the demethylating activity of azacytidine in MDS patients and provide detailed insight into drug-induced demethylation responses.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Azacitidine / analogs & derivatives*
  • Azacitidine / pharmacology
  • Cell Line, Tumor
  • Cytosine / metabolism
  • DNA Methylation / drug effects*
  • Decitabine
  • Genome, Human / genetics
  • Humans
  • Leukemia, Myeloid / genetics*
  • Myelodysplastic Syndromes / genetics
  • Oligonucleotide Array Sequence Analysis

Substances

  • Antineoplastic Agents
  • Decitabine
  • Cytosine
  • Azacitidine