Pediatric leukemia is the most common cause of disease-related death in children and arises through mechanisms that are distinct from most adult cancers. Studies of newborn blood spots reveal that many childhood cancers originate during embryonic development. Unlike typical adult cancers, pediatric leukemias are often driven not by simple DNA mutations, but by gene fusions that include master developmental regulators. While these fusion proteins retain some normal activities, they are “rewired”—interpreting the genome in ways that stall normal development and drive uncontrolled growth. These fusions have been extremely difficult to target therapeutically, though successful interventions have been transformative. Our team proposes using cutting-edge computational tools to identify the specific DNA sequences that elicit different responses in tumor cells and developmentally matched healthy cells. This approach directly links cancer drivers to their gene-regulatory consequences, revealing how specific genes are turned on or off to promote leukemia. By decoding this misregulation, we aim to uncover why developmental gene regulation is uniquely vulnerable to fusion-driven rewiring and potentially identify novel transcriptional drivers of leukemia.