Consistent with the essential role of DOT1L and H3K79 methylation as a critical mechanism to initiate and maintain leukemogenesis in MLL-rearranged leukemia [15,16,17], the MLL-AF9 interaction with DOT1L plays a crucial role in MLL-AF9 transformed leukemia cells, in a similar manner to that seen with inhibition of DOT1L enzymatic activity (Figure 2). This evidence concerns the gene MLLT3 and leukemia.