The genomic landscape of pediatric acute lymphoblastic leukemia 3 Visualizations

Recent studies have identified multiple new subtypes of childhood B- and T-lineage acute lymphoblastic leukemia (ALL) and their initiating drivers, but a detailed understanding of the landscape of genomic alterations across the spectrum of ALL is lacking. Here, using integrated analysis of whole genome, exome and transcriptome sequencing of 2,754 childhood ALL patients, we find that despite a generally low mutation burden, ALL cases harbor a median of 4 somatic driver alterations per sample, with 376 putative driver genes identified that vary in prevalence across ALL subtypes. B-ALL was enriched for Ras pathway and B-cell transcription factor alterations, and T-ALL enriched for NOTCH, PI3K, JAK-STAT, and cell cycle alterations. Most samples harbored at least one rare driver gene alteration, including 73 putative cancer driver genes associated with ubiquitination, SUMOylation, non-coding transcripts and other functions. We identified contrasting patterns of genomic evolution in leukemia subtypes characterized by aneuploidy. In hyperdiploid B-ALL, the commonest form of childhood leukemia, chromosomal gains are acquired early and synchronously, prior to ultraviolet-induced mutation. By contrast, ultraviolet-induced mutations precede copy gains in B-ALL cases with intrachromosomal amplification of chromosome 21 (iAMP21). We also demonstrate prognostic significance of genetic alterations within subtypes. Intriguingly, DUX4- and KMT2A-rearranged subtypes separate into CEBPA/FLT3- or NFATC4-expressing subgroups with potential clinical implications. Together, these results deepen understanding of the ALL genomic landscape and associated outcomes, may influence risk stratification and treatment strategies, and facilitate ALL model development.