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Tumour lysis syndrome (TLS) is an oncological emergency characterized by extensive tumour cell breakdown, leading to the rapid release of intracellular contents into the systemic circulation. In this Primer, Howard and colleagues summarize the epidemiology, pathophysiology, diagnosis and management of TLS.

New therapeutic strategies are needed to improve the cure rate and quality of life in patients with acute lymphoblastic leukaemia. In this Review, Pui and Jeha discuss emerging new treatments that could improve the clinical outcome for these patients.

Acute lymphoblastic leukemias (ALL) with an ETV6::RUNX1 fusion comprise the largest subtype of this cancer, and their optimal treatment strategy remains unclear. Here, the authors perform genomic profiling of 194 ETV6::RUNX1-rearranged pediatric ALL cases, finding two molecular subtypes associated with distinct drug sensitivities.

Mary Relling and colleagues explore the effects of ancestry on the pharmacogenomics of relapse in acute lymphoblastic leukemia. They found that Native American ancestry was associated with risk of relapse but that differences in relapse risk were abrogated by the addition of a single extra phase of chemotherapy.

The survival rate of patients with pediatric cancer has increased considerably due to improved understanding of the biology of cancer subtypes, and the development of targeted therapies. This Review analyzes the recent findings that link pharmacogenomic variations with drug exposure, adverse effects, and efficacy of the emerging new treatments in pediatric oncology.

This paper reports the identification of high-frequency deletions in the Ikaros gene in acute lymphoblastic leukaemia cases that are characterized by BCR-ABL1 translocations. In contrast, BCR-ABL1 CML is not associated with Ikaros deletions in chronic phase patients, but are often acquired during progression to blast crisis. These deletions lead to expression of altered transcripts. In contrast to previous models suggesting that these transcripts result from aberrant alternative splicing, it is shown that the deletions found are due to aberrant RAG-mediated recombination.

The effect of noncoding genetic variation on acute lymphoblastic leukemia treatment response is not fully understood. Here, the authors functionally evaluated variants associated with pharmacological traits and validate the role of rs1247117 in gene regulation impacting therapeutic response.

Pharmacotyping analyses of large cohorts of pediatric acute lymphoblastic leukemia identify correlations between drug sensitivities and clinical outcomes across different genomic subtypes.

Different molecular subtypes defined by specific gene rearrangements have been described for acute lymphoblastic leukaemia (ALL). Here, the authors show that ZNF384 fusion activates FLT3 expression conferring a therapeutic vulnerability for ZNF384- rearranged ALL subtype.

A genomic and transcriptomic analysis of 2,754 childhood acute lymphoblastic leukemias identifies 376 putative driver genes, and associations between disease subtypes and prognosis.

A germline variant associated with acute lymphoblastic leukemia activates an enhancer element resulting in increased GATA3 expression, altered chromatin accessibility and changes in three-dimensional genome organization.

B-cell acute lymphoblastic leukaemia (B-ALL) is a common childhood cancer. Here, the authors conducted a meta-analysis with four genome-wide association studies, totalling 5,321 cases and 16,666 controls of European descent, identifying B-ALL risk loci, whose integration with epigenomic profiling indicates cell-cycle and B-cell development deregulation as central mechanisms in B-ALL susceptibility, often in a subtype-specific fashion.

A large-scale genomics study shows that the cell of origin and founding mutations determine disease subtype and lead to the expression of multiple haematopoietic lineage-defining antigens in mixed phenotype acute leukaemia.

Genome-wide association studies indicate a strong genetic susceptibility to acute lymphoblastic leukaemia in children, though the effect on protein-coding genes is not fully understood. Here Xu and Zhang et al. identify a missense variant in CDKN2Awhich reduces tumour suppression.

Yang and colleagues perform a network system–pharmacology approach and clinical data integration, and identify LCK and BCL2 signaling as the molecular determinants of dasatinib response in pediatric and adult patients with T-ALL.

Autry et al. combine genome-wide genomic, epigenetic and transcriptomic analyses in an integrated polygenomic approach to identify mechanisms of glucocorticoid resistance in acute lymphoblastic leukemia.

Analysis of 1,988 cases of B-cell acute lymphoblastic leukemia characterizes 23 subtypes defined by genomic features and shows that two of the subtypes have frequent PAX5 alterations.

A risk variant located at 9p21.3 is associated with cancer risk in pediatric B-cell precursor acute lymphoblastic leukaemia. Here, the authors show that this variant affects the gene expression of the tumour suppressor gene Cdkn2b.

Jun Yang and colleagues perform targeted sequencing of NUDT15 and identify loss-of-function variants associated with thiopurine intolerance. Functionally, they show that NUDT15 inactivates thiopurine metabolites, providing a mechanism to explain the association between NUDT15 loss-of-function variants and thiopurine toxicity.

A genome-wide, high-resolution single nucleotide polymorphism array analysis of a large number of acute lymphoblastic leukaemia samples identifies a number of genomic changes. These include alterations in the genes encoding Pax5 and other regulators of B-cell development and differentiation.

This work shows that treatments used for acute myeloid leukaemia and targeted therapies could be used for early T-cell precursor acute lymphoblastic leukaemia.

William Evans and colleagues find that the proinflammatory genes CASP1 and NLRP3 are expressed at higher levels in primary acute lymphoblastic leukemia cells that are resistant than in those that are sensitive to glucocorticoid treatment. They find that CASP1 mediates glucocorticoid resistance through cleavage of the glucocorticoid receptor.

Linda Holmfeldt, Lei Wei et al. report whole-genome and exome sequencing of 40 childhood hypodiploid acute lymphoblastic leukemias.

Charles Mullighan, Jinghui Zhang and colleagues characterize a subtype of B-progenitor acute lymphoblastic leukemia with deregulated DUX4 and ERG. They find that aberrant DUX4 activation results in loss of ERG function, either through deletion or by the induction a novel transforming ERG isoform, ERGalt, that inhibits wild-type ERG activity.

Anna Andersson, Tanja Gruber, James Downing and colleagues report a genomic analysis of infant acute lymphoblastic leukemias with MLL rearrangements. They identify recurrent activating mutations in tyrosine kinase, phosphatidylinositol 3-kinase and RAS pathway genes but find that these mutations were often present in minor subclones and lost at the time of relapse.

Herein, advances in our understanding of the genomic landscape of childhood acute lymphoblastic leukaemia (ALL), encompassing both somatic and germline alterations, are reviewed. The clinical implications of these alterations, particularly those in the germ line, are discussed with regard to susceptibility to ALL, treatment responses and therapy-related toxicities.

Jun Yang and colleagues show that common variants in GATA3 are associated with risk of Ph-like acute lymphoblastic leukemia (ALL). They further show that these variants are associated with variation in GATA3 expression levels and with risk of ALL relapse.

In three different subtypes of B-cell lymphomas, two papers now report frequent somatic mutations in CREBBP and EP300, present in primary tumours or acquired at relapse. These genes encode related acetyltransferases that mainly function to regulate gene expression by acetylating histones and other transcriptional regulators. The mutations found inactivate these activities and thus alter chromatin regulation of gene expression, as well as proliferation and potentially the response to therapeutic drugs.

Loss of mismatch repair (MMR) genes is associated with poor cancer prognosis and has been reported to occur through genetic alterations that directly affect the expression of MMR genes such as MSH2. This report identifies a subset of leukemia patients with reduced levels of MSH2 protein but without alterations in the MSH2 gene, and it identifies concurrent deletions in regulators of MSH2 stability as potential contributors to the MSH2 deficiency and associated drug resistance in this and other cancers.

Lars Bullinger, Jinghui Zhang, Jeffery Klco, James Downing and colleagues report a detailed genomic analysis of pediatric and adult core-binding factor acute myeloid leukemias (CBF-AMLs). They identify recurrent mutations in CCND2, MGA, DHX15 and ZBTB7A and highlight dramatic differences in the landscape of cooperating mutations between different CBF-AML subtypes.

Mary Relling and colleagues report results of a genome-wide association study of childhood acute lymphoblastic leukemia (ALL) and its subtypes, identifying a specific association between common variants in ARID5B and B-hyperdiploid ALL.

Charles Mullighan and colleagues report a recurrent rearrangement of CRLF2 in B-progenitor and Down syndrome-associated acute lymphoblastic leukemia. Their genetic and functional evidence indicates that CRLF2 cooperates with activated JAK2 to promote leukemogenesis.