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The genomic landscape of pediatric acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer and arises from B- or T-lineage lymphocyte precursors. ALL comprises dozens of subtypes, and genomic analyses have largely been performed within these subtypes. Here we analyze pediatric ALL genomes across all subtypes, including 768 whole genomes, 1,729 exomes, and 1,889 transcriptomes in 2,754 patients. Most ALL subtypes harbor 4 or more driver alterations per sample, similar to adult cancers, despite low mutation burdens. Hyperdiploid B-ALL copy gains are likely acquired early and synchronously, with copy gains occurring before ultraviolet-induced mutations. By contrast, ultraviolet-induced mutations precede copy gains in iAMP21 B-ALL. Overall, we identified 378 putative ALL driver genes. Most driver alterations vary in prevalence across ALL subtypes, with B-ALL enriched for Ras and B-lineage-related alterations, and T-ALL enriched for PI3K, JAK, and cell cycle alterations. Most B-ALL (54.3%) and T-ALL (51.2%) samples bear at least one rare driver gene alteration (present in less than 2% of samples), including 30 putative novel cancer driver genes associated with ubiquitination, SUMOylation, non-coding, and other functions. Known or novel alterations associated with poor outcomes in specific subtypes include TBL1XR1 alterations in ETV6-RUNX1 patients, CREBBP in Ph-like-CRLF2, SETD2 in hyperdiploid, and PTEN in TAL1 patients. Intriguingly, DUX4 and KMT2A subtypes separate into CEBPA/FLT3- or NFATC4-expressing subgroups with potential clinical implications. Together, these results deepen understanding of ALL etiology and outcomes, and facilitate ALL model development.

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID Description Technology Samples
EGAD00001008134 Illumina HiSeq 2500 Illumina NovaSeq 6000 16
EGAD00001008193 Illumina HiSeq 2500 598
EGAD00001008268 Illumina HiSeq 2500 700
EGAD00001008290 Illumina HiSeq 2500 650
EGAD00001008600 Illumina HiSeq 2000 278
EGAD00001010270 Illumina HiSeq 2000 2
Publications Citations
Acute lymphoblastic leukemia displays a distinct highly methylated genome.
Nat Cancer 3: 2022 768-782
The genomic landscape of pediatric acute lymphoblastic leukemia.
Nat Genet 54: 2022 1376-1389