The finding that DOT1L plays a key role in the development of MLL-rearranged leukemia-induced intense research in the field of drug discovery, aimed to design and synthesize small molecular inhibitors foreseeing blockade of DOT1L aberrant activity (Figure 2), caused by the acquired capability of MLL fusion proteins to interact with this methyltransferase (Okada et al., 2005; Bitoun et al., 2007; Mohan et al., 2010; Park et al., 2010). This evidence concerns the gene DOT1L and leukemia.