A genomic analysis of the clonal origins of relapsed acute lymphoblastic leukemia (ALL) reveals that relapse is often driven by new genetic alterations acquired during treatment. The study analyzed 61 ALL patients, comparing diagnosis and relapse samples to identify copy number abnormalities (CNAs) and loss of heterozygosity (LOH). Most relapse samples showed different CNAs compared to diagnosis, with relapse-associated CNAs affecting genes involved in cell cycle regulation and B-cell development. These findings suggest that relapse cells may originate from an ancestral clone present at diagnosis, rather than from the primary leukemia cells. The study also identified common clonal relationships between diagnosis and relapse samples, with many relapse clones derived from pre-diagnosis precursor cells. Key genes affected by relapse-associated CNAs include CDKN2A/B, ETV6, and regulators of B-cell development. The results highlight the complexity of relapse mechanisms, involving multiple genetic alterations and pathways, rather than a single lesion. These findings provide insights into the genetic basis of relapse and suggest potential therapeutic targets. The study underscores the importance of understanding the clonal evolution of ALL to develop effective treatments for relapsed cases.A genomic analysis of the clonal origins of relapsed acute lymphoblastic leukemia (ALL) reveals that relapse is often driven by new genetic alterations acquired during treatment. The study analyzed 61 ALL patients, comparing diagnosis and relapse samples to identify copy number abnormalities (CNAs) and loss of heterozygosity (LOH). Most relapse samples showed different CNAs compared to diagnosis, with relapse-associated CNAs affecting genes involved in cell cycle regulation and B-cell development. These findings suggest that relapse cells may originate from an ancestral clone present at diagnosis, rather than from the primary leukemia cells. The study also identified common clonal relationships between diagnosis and relapse samples, with many relapse clones derived from pre-diagnosis precursor cells. Key genes affected by relapse-associated CNAs include CDKN2A/B, ETV6, and regulators of B-cell development. The results highlight the complexity of relapse mechanisms, involving multiple genetic alterations and pathways, rather than a single lesion. These findings provide insights into the genetic basis of relapse and suggest potential therapeutic targets. The study underscores the importance of understanding the clonal evolution of ALL to develop effective treatments for relapsed cases.