Cancer is caused by DNA mutations and genomic aberrations, collectively referred to as DNA damage. The etiology of DNA damage that drives pediatric cancers is often unknown given the minimal influence of exogenous carcinogens. This research seeks to determine sources of DNA damage that impact pediatric genomes. We also propose to identify genome-protective signaling pathways, known as DNA damage responses, that are activated in cancer cells. Our research will evaluate the cellular contexts in which DNA damage responses are effective therapeutic targets for pediatric cancer. In line with the goals of the Children’s Discovery Institute and Siteman Kids, the proposed studies will leverage collaborative, cutting-edge science in order to develop novel, targeted therapies for childhood cancer.
· Identify therapeutic targets in leukemia with high levels of enzyme APOBEC3A, which can induce DNA damage.
· Elucidate DNA damage responses in infant leukemia with rearrangements in the KMT2A (previously MLL1) gene.
· Determine the impact of the APOBEC3A enzyme on hematopoietic cell development and transformation.
These studies will elucidate etiologies of DNA damage and resulting DNA damage responses to enable discovery of genetic drivers, biomarkers, and therapeutic targets in childhood cancer. The overall goal of this research is to develop new treatments to improve outcomes for pediatric oncology patients.