Role of Polycomb Repressive Complex 2 (PRC2) Mutations in Juvenile Myelomonocytic Leukemia

Background

Currently, bone marrow transplantation is the only cure for Juvenile Myelomonocytic Leukemia (JMML), an aggressive myeloproliferative neoplasm in young children. However, approximately 50% of children still die from the disease despite the aggressive treatment. Mutations leading to activated PTPN11 and/or PAS signaling have been discovered to play a key role in JMML, but there is not a complete understanding of the molecular pathogenesis of the disease. This has hindered the efforts to develop more effective and less aggressive therapies. However, recent studies have identified recurrent somatic mutations that also occur with PTPN11/RAS pathway gene mutations in JMML.

Project Goal

Emily will be working to generate a mouse model for cooperating mutations in PTPN11 and EZH2, and PRC2 component that is mutated in JMML. This will characterize the disease phenotype in the double mutant mice. The goal is to provide evidence for functional cooperation of PRC2 mutations in JMML pathogens, and provide an improved animal model system to further investigate JMML, and develop novel drugs for this leukemia.