Acute myeloid leukemia (AML) is a highly aggressive cancer arising from the white blood cells that can affect both children and adults. The five-year overall survival rate for adult patients with AML in the United States remains less than 30%, and only marginal improvements in patient outcomes have been achieved in the last 30 years. The implementation of advanced DNA sequencing technology has led to a dramatic increase in our understanding of the underlying molecular basis of AML. Remarkably, we have discovered that many of the alterations that lead to the development of AML in patients are not due to mutations within genes themselves but result from abnormal expression of growth-promoting genes. Our lab and others have shown that developing treatments to target this altered gene expression is possible and represents an effective new way to treat AML. Oncogenic fusions in a gene called MLL are found in both adult and pediatric AML. We recently identified the critical importance of a protein called ENL, which maintains the altered level of gene expression observed in MLL-fusion AML. Our work will build on this discovery by further characterizing the function of the ENL protein and increasing our understanding of why AML cells are so dependent on ENL for their sustained growth. In particular, little is known of how ENL interacts with MLL fusions. It is also unknown how ENL interacts with DOT1L1 and BRD4, which are also important in the context of MLL fusions and which are targeted by drugs that are in clinical development. We will examine how treatments aimed at targeting ENL may be incorporated into existing treatment strategies. We will also evaluate the cancer cells for potential mechanisms of treatment-resistance, given that patients with AML can often develop resistance to treatments that are initially effective. This will also allow us to better predict which patients will most likely benefit from this type of treatment. The research will incorporate multiple lines of investigation and approaches, including genome editing and a number of experimental models of AML in the laboratory. With a better understanding of the role of ENL in AML, and the subsequent targeting of this protein, it is our goal that new, more effective and safer treatment strategies will be developed for patients with AML.