The methyltransferase domain of DNMT1 is an essential domain in acute myeloid leukemia independent of DNMT3A mutation.

Aberrant DNA methylation patterns are a prominent feature of cancer. Methylation of DNA is mediated by the DNA methyltransferase (DNMT) protein family, which regulates de novo (DNMT3A and DNMT3B) and maintenance (DNMT1) methylation. Mutations in DNMT3A are observed in approximately 22% of acute myeloid leukemia (AML). We hypothesized that DNMT1 or DNMT3B could function as a synthetic lethal therapeutic strategy for DNMT3A-mutant AML. CRISPR-Cas9 tiling screens were performed to identify functional domains within DNMT1/DNMT3B that exhibited greater dependencies in DNMT3A mutant versus wild-type cell lines. Although increased sensitivity to DNMT1 mutation was observed in some DNMT3A mutant cellular models tested, the subtlety of these results prevents us from basing any conclusions on a synthetic lethal relationship between DNMT1 and DNMT3A. Our data suggests that a therapeutic window for DNMT1 methyltransferase inhibition in DNMT3A-driven AML may exist, but validation in more biologically relevant models is required.