title: DNA Methyltransferases Demonstrate Reduced Activity against Arabinosylcytosine: Implications for Epigenetic Instability in Acute Myeloid Leukemia.
abstract: 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.
authors.affiliation: Department of Medicine and ‡Department of Biochemistry & Biophysics, Perelman School of Medicine at the University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Nabel
authors.affiliation: Department of Medicine and ‡Department of Biochemistry & Biophysics, Perelman School of Medicine at the University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
authors.forename: Jamie E
authors.initials: JE
authors.lastname: DeNizio
authors.affiliation: Department of Medicine and ‡Department of Biochemistry & Biophysics, Perelman School of Medicine at the University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
authors.forename: Martin
authors.initials: M
authors.lastname: Carroll
authors.affiliation: Department of Medicine and ‡Department of Biochemistry & Biophysics, Perelman School of Medicine at the University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
authors.forename: Rahul M
authors.identifier: 0000-0002-7689-5678
authors.initials: RM
authors.lastname: Kohli
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000378:metabolism* / Q000627:therapeutic use; D003561:Cytarabine / Q000378:metabolism* / Q000627:therapeutic use; D015254:DNA Modification Methylases / Q000378:metabolism*; D044127:Epigenesis, Genetic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*
chemical_list: D000964:Antimetabolites, Antineoplastic; D003561:Cytarabine; D015254:DNA Modification Methylases