New Investigator Research Grant Program

Acute myeloid leukemia (AML) is an aggressive blood cancer, and patients whose leukemia carries mutations in the TP53 gene have very poor outcomes. These patients often do not respond well to currently available treatments and survival is usually measured in months. Thus, TP53-mutant AML represents one of the most urgent unmet needs in leukemia research. In prior work, I found that TP53-mutant AML cells rely on a metabolic pathway called the mevalonate pathway to survive therapy. This pathway produces molecules that help activate proteins needed for leukemia cell growth and survival. In preliminary studies, I identified one of these proteins, called RhoA, as a potential key driver of drug resistance in TP53-mutant AML. Importantly, RhoA can be blocked with experimental drugs, making it a promising new treatment target. In this project, I will test whether blocking RhoA can make TP53-mutant AML cells more sensitive to AML therapies. I will study this using newly developed laboratory models of TP53-mutant AML, primary leukemia samples from patients, and mouse models that closely mimic human disease. I will also investigate why TP53-mutant AML depends on RhoA, focusing on how loss of normal p53 function may allow RhoA to become abnormally activated during treatment. If successful, this project will identify RhoA as a new therapeutic vulnerability of TP53-mutant AML and provide the preclinical evidence needed to support future clinical trials testing RhoA-targeted strategies.