DNA Methyltransferases Demonstrate Reduced Activity against Arabinosylcytosine: Implications for Epigenetic Instability in Acute Myeloid Leukemia

Arabinosylcytosine (araC) is a mainstay in the initial treatment of acute myeloid leukemia (AML), although relapses are common. Given the recent recognition of altered DNA methylation patterns in relapsed AML, we considered whether araC, which acts by incorporation into DNA, could itself perturb methylation dynamics. To explore this possibility, we examined several DNA methyltransferases and find that araC embedded in DNA is consistently methylated with an efficiency diminished relative to that of deoxycytidine. Importantly, with the human maintenance methyltransferase DNMT1, the extent of araC methylation is reduced by more than ∼200-fold. These observations support a model whereby araC treatment may itself contribute to locus-specific, passive DNA demethylation in relapsed AML.