For instance, the well-characterized histone methyltransferase DOT1L is an upstream epigenetic regulator of HOXA9. Through its recruitment to the HOXA locus via KMT2A-r fusion proteins, DOT1L causes hypermethylation of the lysine 79 residue of histone H3 (11), and selective DOT1L inhibitors prevent the development of KMT2A-r leukemias (12, 13). Here, DOT1L is linked to leukemia.