Abstract Down syndrome (DS) is one of the strongest risk factors for acute lymphoblastic leukemia (ALL), conferring a 20-fold increased risk compared to children without DS. Survival for children with DS-ALL remains 10-20% lower than that of non-DS-ALL patients, due to both relapse and treatment-related mortality. Therefore, there is an unmet need to understand the biology of DS-ALL. To address this, we have recently led collaborative efforts to perform on the largest genomic profiling studies of DS-ALL, through the INCLUDE and KidsFirst initiatives. Capitalizing on this invaluable NIH investment, we proposes to apply our novel systems biology analyses to these datasets to characterize signaling networks in DS-ALL with a particular focus on features that distinguish DS-ALL from ALL in children without DS. This project will address fundamental questions of why children with DS have an increased risk of ALL and how their leukemia differs from that of children without DS. Findings from this study may lead to new insights into genes driving DS-ALL and may guide development of targeted therapies for this unique but vulnerable group of patients.