A pivotal study led by St. Jude Children’s Research Hospital and Princess Margaret Cancer Centre reveals that the developmental stage of B cells at leukemia onset influences treatment outcomes in pediatric B-cell acute lymphoblastic leukemia (B-ALL). Using integrated single-cell sequencing and genomic mapping, the researchers identified a broader heterogeneity in leukemia cell origins than previously recognized, challenging existing paradigms. This mechanistic insight holds promise for improving risk stratification and targeted therapies in childhood leukemia.