New Investigator Research Grant Program

FLT3-ITD is a frequent mutation in an aggressive form of blood cancer called acute myeloid leukemia (AML). FLT3-ITD mutations lead to high rates of relapse. FLT3 inhibitors (FLT3i) are a standard treatment for FLT3-ITD AML. FLT3i often work by causing the leukemia cells to mature into non-cancerous cells (differentiation). My research has improved our understanding of the mechanisms that underlie FLT3i response and resistance. The degree of differentiation achieved by FLT3i alone is not sufficient for sustained remissions as the underlying leukemia stem cell remains. How FLT3 inhibitors cause this change in the leukemia cells is not well understood. Acute promyelocytic leukemia, a variant of AML, has been essentially cured with highly effective differentiation therapy without the use of traditional “cytotoxic” chemotherapy. My long-term goal is to identify similar therapies for FLT3-ITD AML. We found that FLT3i reduce the levels of another protein, EZH2. EZH2 is important for keeping leukemia stem cells in a stem cell state. We also observed that RAS mutations that drive resistance to FLT3i seem to also limit their effectiveness in reducing EZH2. In this study, we aim to understand the specific pathways by which FLT3i reduce EZH2 and investigate how mutations in RAS affect the differentiation response with FLT3i. These findings will guide future studies to enhance targeted therapy for FLT3-ITD AML.