Investigating the Role of Nucleophosmin as a Novel Caspase-2 Target in Pediatric Leukemia

Background

The tumor suppressor caspase-2’s 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 but it has also been shown to prevent cell division. Therefore, caspase-2 may protect against leukemia by apoptosis or by stopping cell division.

However, it is not clear how caspase-2 carries out these functions. Caspase-2 generally functions by cleaving specific proteins to increase or decrease their activity. We have identified NPM1 as a novel target for caspase-2. NPM1 is commonly altered in leukemia and is mutated in up to 12% of cases of pediatric AML. This protein has many functions including important roles in regulating apoptosis and cell division. Therefore, we propose that caspase-2-mediated NPM1 results in death or arrest of leukemia cells.

Project Goal

This project will explore this event to answer the following questions: (1) Where in the NPM1 protein does caspase-2 cleave? (2) Does cleaving NPM1 lead to cell death or apoptosis? (3) What are the consequences of cleaving NPM1? (4) Do mutations in NPM1 found in AML block the ability of caspase-2 to cleave the protein? These studies will help us understand how caspase-2 inhibits cancer growth and if caspase-2 or NPM1 are viable drug targets for pediatric leukemia.