Pediatric acute myeloid leukemia (AML) stands as the most prevalent childhood malignancy, yet despite incremental progress in supportive care and risk stratification, the development of groundbreaking therapies enhancing survival has been sluggish. This collaborative team is now dedicated to addressing this challenge by focusing on the distinctive mutational landscape of pediatric AML. Their goal is to create advanced mouse models that intricately capture the diverse genetic and contextual factors influencing the development of AML. Leveraging induced pluripotent stem cells, the team plans to generate mouse models expressing pediatric AML driver oncoproteins and cooperating mutations. The study will investigate epigenetic vulnerabilities through CRISPR/Cas9 screens and identify fusion protein-specific metabolic profiles. This innovative approach, combining novel models, functional screens, and state-of-the-art metabolomic profiling tools, uniquely positions the collaborative group to significantly contribute to the comprehension and targeted treatment of high-risk pediatric AML, effectively addressing the pressing need for improved modeling and therapeutic strategies.