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. Here, DNMT3A is linked to acute myeloid leukemia.