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Genetic drivers of vulnerability and resistance in relapsed acute lymphoblastic leukemia

2016; National Academy of Sciences; Volume: 113; Issue: 40 Linguagem: Inglês

10.1073/pnas.1613836113

1091-6490

Sydney X. Lu, Omar Abdel‐Wahab,

Lung Cancer Research Studies

Relapsed acute lymphoblastic leukemia (ALL) is associated with very poor outcomes despite modern therapies in both children and adults (1⇓–3). In PNAS, Oshima et al. elucidate both the mutational landscape as well as patterns of clonal evolution of pediatric relapsed ALL and identify potential therapeutic targets in this challenging illness (4). Although prior studies have performed SNP array analysis (SNPa), whole-exome sequencing (WES), whole-genome sequencing (WGS), and/or mRNA sequencing (RNA-seq) at diagnosis and relapse (Table 1), the majority of prior analyses have focused on relapsed pediatric B-ALL specifically. Here, the authors performed WES of 55 pediatric ALL patients (33 T-cell ALL and 22 B-cell precursor ALL) at diagnosis, remission, and relapse and complemented these data with RNA-seq of a validation cohort of 49 paired diagnosis/relapse B-ALL patient samples. This analysis has allowed for reevaluation of the pattern of clonal evolution in relapsed ALL and revealed that the majority of relapsed ALLs (∼85%) contain only some of the genetic lesions present in the major clone at diagnosis. In contrast, only in 4% of cases did the relapsed clones contain all mutations present at diagnosis plus additional secondary relapse-specific lesions. Together, these data identify that linear evolution is rarely involved in tumor progression in ALL and that relapsed ALL originates primarily as derivatives of ancestral subclones related to, but distinct from the main leukemic population present at diagnosis. This conclusion extends previous observations of the clonal basis of relapsed ALL by Mullighan et al. (5), which used SNPa to reveal that cells responsible for relapse were often minor subpopulations of the cells responsible for initial disease (Table 1). View this table: Table 1. Genomic analysis of relapsed ALL In addition to evaluating the clonal … [↵][1]1To whom correspondence should be addressed. Email: abdelwao{at}mskcc.org. [1]: #xref-corresp-1-1