The study by Charles G. Mullighan and colleagues investigates the genomic origins of relapsed acute lymphoblastic leukemia (ALL) in children. They performed genome-wide DNA copy number analyses on matched diagnosis and relapse samples from 61 patients with ALL. The results show that most relapse samples exhibit different patterns of genomic copy number abnormalities (CNAs) compared to diagnosis samples, with these abnormalities preferentially affecting genes involved in cell cycle regulation and B cell development. Despite the genetic relationship between diagnosis and relapse samples, most relapse samples lack some CNAs present at diagnosis, suggesting that the cells responsible for relapse are ancestral to the primary leukemia cells. Backtracking studies further demonstrate that the relapse clone was often present as a minor sub-population at diagnosis. The study identifies several common pathways, such as cell cycle regulation and B-cell development, as targets for therapeutic intervention. These findings provide insights into the molecular lesions responsible for ALL relapse and highlight the complexity of the relapse process.The study by Charles G. Mullighan and colleagues investigates the genomic origins of relapsed acute lymphoblastic leukemia (ALL) in children. They performed genome-wide DNA copy number analyses on matched diagnosis and relapse samples from 61 patients with ALL. The results show that most relapse samples exhibit different patterns of genomic copy number abnormalities (CNAs) compared to diagnosis samples, with these abnormalities preferentially affecting genes involved in cell cycle regulation and B cell development. Despite the genetic relationship between diagnosis and relapse samples, most relapse samples lack some CNAs present at diagnosis, suggesting that the cells responsible for relapse are ancestral to the primary leukemia cells. Backtracking studies further demonstrate that the relapse clone was often present as a minor sub-population at diagnosis. The study identifies several common pathways, such as cell cycle regulation and B-cell development, as targets for therapeutic intervention. These findings provide insights into the molecular lesions responsible for ALL relapse and highlight the complexity of the relapse process.