Deciphering the role of p53 signaling in NPM1-mutant AML
Christine Zhang
PhDWashington University in St. Louis
Project Term: July 1, 2023 - June 30, 2025
NPM1c and TP53 mutations are exclusive in acute myeloid leukemia (AML) despite both being commonly present in patients, suggesting a fitness disadvantage for cells with co-occurring mutations. However, the mechanisms underlying this exclusivity have not been explored. This project will utilize novel models to dissect the importance of TP53 signaling in NPM1c+ (pre)-leukemic stem cells. Generated results may highlight therapeutic opportunities for improved risk management of NPM1c+ AML patients.
Specific genetic aberrations is a hallmark of acute myeloid leukemia. These alterations correlate well with disease prognosis and patient survival. Mutations in Nucleophosmin1 are highly prevalent in AML, occurring in ~30% of AML patients. Over 90% of AML-associated NPM1 mutations give rise to a mislocated protein (NPM1c), transforming pre-leukemic cells by activating HOX genes. This mutation is believed to be a disease-defining event acquired by leukemic stem cells (LSCs). Therefore, the presence of NPM1c during remission can predict relapse. Despite extensive studies, the relapse rate of NPM1c+ AML remains high (approximately 50% of patients). The high relapse rate indicates that the current treatment regimen is inefficient in eliminating NPM1c+ LSCs, emphasizing the need for improved therapeutic strategies.
Mutations acquired by LSCs bestow these cells with a survival advantage via various mechanisms. Conversely, if combinations of common AML mutations are never observed this suggests a negative interaction that is detrimental for the leukemic cells. Thus, understanding mutational exclusivity for NPM1c+ AML patients may highlight strategies to eliminate NPM1c+ LSCs. By analyzing over 10,000 AML patient samples from public databases, we identified a significant mutational exclusivity between NPM1c and TP53 mutations. Using novel model systems, we demonstrated the importance of TP53 to NPM1c+ leukemic and pre-leukemic cells in a HOX-independent manner. We propose to investigate the underlying mechanisms by which TP53 guards the fitness advantage of NPM1c+ cells. Future studies will functionally evaluate the therapeutic potentials of any identified molecular regulators crucial to the p53-mediated survival advantage of NPM1c+ cells in obliterating the mutant cells. Results generated from this project may provide rationales for improved therapeutic management of NPM1c+ AML patients.