Collectively, our data argue that the FLT3-ITD signaling and PRC2 pathways, are more sensitive to disruptions of MLL-fusion-mediated gene activation than the canonical oncogenic drivers in MLL-r, FLT3ITD leukemias, defining a new molecular understanding of how MLL-fusions cooperate with other oncogenic factors to induce leukemia. This evidence concerns the gene KMT2A and leukemia.