Investigating the interplay between nucleophosmin and caspase-2 in determining chemosensitivity in childhood AML
Mentor: Dr. Helen Heslop
Nucleophosmin (NPM1) is one of the most frequently mutated genes in pediatric AML and patients with this mutation tend to respond better to chemotherapy. NMP1 regulates a number of essential cellular functions which are dependent on NPM1 being able to localize to the nucleolus. Mutated NPM1 is located in the cytoplasm, which makes the cancer cells more sensitive to chemotherapy. Thus disruption of the normal NPM1 function in the nucleolus can sensitize cells. Therefore, NPM1 represents a promising target for pediatric AML. This project aims to understand how NPM1 works with a protein called caspase-2 work to prevent or limit pediatric leukemia. Caspase-2 is a tumor suppressor and its levels are decreased in the childhood forms of acute leukemia including T-lineage acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML). The main role of caspase-2 is to induce a form of cell death called apoptosis in diseased or damaged cells. Our data demonstrates that DNA damage induces NPM1-dependent caspase-2 activation in the nucleolus. We propose that NPM1-mediated regulation of the caspase-2 pathway is a critical node in the regulation of AML cell death and survival. This project will explore this event to answer the following questions: (1) Does mutated NPM1 activate caspase-2 in AML cells? (2) Does blocking NPM1 increase or decrease caspase-2 dependent cell death in AML cells? We will use a range of biochemical and cell-based techniques to explore these questions. These studies will help us understand how mutations in NPM1 increase sensitivity to chemotherapy and if caspase-2 or NPM1 are viable drug targets for pediatric leukemia. In undertaking these investigations, we hope to make important contributions to our basic understanding of the roles of caspase-2 and NPM1 in regulating apoptosis.