Demethylation demystification

Abstract

The ability of the DNA methyltransferase inhibitors (DNMTi) to induce terminal differentiation in fibroblasts was first noted by Taylor and Jones in 1979; Silverman and Holland reported hematologic improvement in patients with myelodysplastic syndrome (MDS) in 1993. That azacitidine improves survival in patients with high-risk MDS and acute myeloid leukemia with MDS features compared with a combined comparator group of supportive care, low-dose cytarabine, and intensive cytarabine plus anthracycline, while inducing trilineage normalization in approximately 15% of patients makes the development of more potent, more specific drugs that behave like azacitidine imperative. The question is, how do the azanucleosides behave?

In this Rube Goldberg contraption, leukemic cells are entered at the “Start” arrow, treated with an azanuceloside analog, and emerge as normal neutrophils. Along the way, a variety of epigenetic targets and DNA damage and repair pathways are encountered. Klco et al illustrate that despite state-of-the-art genomic technology, the mechanisms accounting for the clinical activity of DNMT inhibitors in myeloid leukemias remain complex and unclear.