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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.

Charles Mullighan, Stephen Hunger, Jinghui Zhang and colleagues report a genomic analysis of 264 pediatric and young adult T-lineage acute lymphoblastic leukemia (T-ALL) samples. They identify 106 candidate driver genes, 53 of which have not been described previously in pediatric T-ALL, as well as associations between mutations and disease stage or subtype.

Here, the authors describe a potent and selective CK1a molecular glue degrader with a broad antiproliferative potency. Crystallographic data provide rationale for the high degradation efficacy displayed by this compound.

Here, the authors identify PHF6 as a dependency in SMARCB1-deficient rhabdoid cancers. Mechanistically, this study suggests a regulatory role for PHF6 in recruiting SWI/SNF complexes to enable RNA polymerase progression.

Iacobucci et al. present the single-cell transcriptomic profile of patients with B cell acute lymphoblastic leukemia, report enriched multipotency and develop a multipotency score that is associated with worse survival in pediatric patients.

Marshall Horwitz, Charles Mullighan, Kenneth Offit and colleagues report the identification of a recurrent germline PAX5 mutation in families with pre–B cell acute lymphoblastic leukemia. They also identify sporadic cases of this leukemia with the same mutation that arose somatically.

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.

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.

Comprehensive genomic and transcriptomics analyses of more than 1,300 cases of childhood T-lineage acute lymphoblastic leukaemia identify 15 distinct subtypes that are associated with specific outcomes.

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

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.

This algorithm uses the soft-clipped, unaligned parts of a sequence read to map structural variation in cancer genomes with high predictive accuracy.

The effects of chromosomal translocations involving the mixed-lineage leukemia (MLL) locus on gene expression regulation remain to be explored. Here, the authors find that MLL oncoproteins support lineage-switching events through dynamic chromatin binding.

Antigen escape relapse remains a major obstacle when treating B-cell malignancies with immunotherapies. Here, the authors show that IKAROS regulates the surface expression of CD19 and CD22, revealing a mechanism by which B-cell cancers evade targeted immunotherapies.

A new study identifies recurrent mutations in the purine biosynthesis gene phosphoribosyl pyrophosphate synthetase 1 (PRPS1) in relapsed acute lymphoblastic leukemia (ALL). This work highlights the importance of this pathway in the pathogenesis of relapse and suggests an approach to predicting and circumventing resistance in ALL.

Analysis of genomic and clinical features of acute erythroid leukemia in comparison to other myeloid disorders supports its distinct classification, defines subgroups and suggests therapeutic vulnerabilities.

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.

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

The genetic basis of myelodysplasia has long been enigmatic, with few common targets of mutation known. A new study reports common mutations in the TET2 gene in myelodysplasia and related myeloid malignancies, suggesting that TET2 has an important role in hematopoiesis and in the pathogenesis of this disease.

Many fusion oncoproteins (FOs) form condensates, some form in the nucleus and regulate gene expression while others form in the cytoplasm and promote cell signaling. In this work, the authors report the analysis of physicochemical features to enable prediction of FO condensation behavior.

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.

Here the authors identify and characterize the development and function of an IFN-γ-producing CD8αβ⁺ subset of γδ T cells that contributes to malignancy.

Acute lymphoblastic leukaemia is characterized by chromosomal rearrangements. Here, the authors carry out RNA-sequencing on a large cohort of patients and identify recurrent rearrangements of MEF2D, which lead to increased transcriptional activity of the gene, and cellular transformation in vitro.

Genetic heterogeneity and clonal evolution contribute to cancer progression. Here Ma et al.use deep whole-exome sequencing to identify recurrently mutated pathways and clonal architecture in pediatric acute lymphoblastic leukaemia, shedding light on the evolutionary trajectory from diagnosis to relapse

Genomic and transcriptomic analyses of chronic lymphoproliferative disorder of natural killer cells identifies somatic gain-of-function mutations in the chemokine gene CCL22 with cell-extrinsic effects. Mutations caused biased signaling downstream of the G-protein-coupled receptor for CCL22 and deregulated interactions with the hematopoietic microenvironment.

Tan and colleagues conducted a single-cell multiomic analysis of T cell acute lymphoblastic leukemia and identified a treatment-resistant subpopulation of bone marrow progenitor-like blasts associated with poor outcomes.

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.

Analysing human B-cell acute lymphoblastic leukaemias, this study maps the genetic heterogeneity of cells within a given tumour sample and the evolutionary path by which different subclones have emerged. Leukaemia-initiating cells that transplant the disease mirror the genetic variegation of the bulk tumours, providing insights into the heterogeneity of these functional subpopulations at the genetic level. This has implications for therapeutic approaches targeting the tumours and specifically leukaemia-initiating cells.

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.

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

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.

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.

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

The retinoblastoma genome is shown to be stable, but multiple cancer pathways are identified that are epigenetically deregulated, providing potential new therapeutic targets.

Paediatric therapy-related myeloid neoplasms (tMN) have a dismal prognosis and have not been comprehensively profiled. Here the authors characterise the molecular landscape of 84 paediatric tMN patients, and find that, unlike adult tMNs, these do not emerge from pre-existing clones and that MECOM dysregulation is frequent.

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.

Farrar and colleagues perform an extensive analysis of Ncor1/2 function in B cell development. Loss of both genes results in defective pre-BCR signaling, increased accessibility of STAT5 chromatin motifs and inappropriate Rag gene expression, leading to accelerated leukemic transformation.

Wilms tumour is a rare renal neoplasm that primarily affects children but the genomic changes responsible for its development are currently largely unknown. In this study, the authors identify somatic mutations of the MLLT1gene that are potentially involved in the aetiology of a subset of Wilms tumours.

Proteins involved in epigenetic regulation are frequently mutated in several paediatric cancers. Here, Huether et al.characterize the somatic mutation frequency across 21 paediatric cancer subtypes by sequencing 633 epigenetic genes in over 1,000 tumours; generating a rich data set for investigating epigenetic dysregulation.

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.

Challenges in batch normalization and data integration limit the comparison of existing mass cytometry datasets. Here, the authors report CytofIn that can integrate mass cytometry datasets from the public domain and reveal cellular features associated with immune oncology by analyzing five public cancer datasets.

Interleukin-7 receptor alpha (IL7Ra) is important for lymphoid cell development but its role in leukaemogenesis is not clear. Here, the authors generate a knock-in murine model to show that activating mutations in IL7Ra can initiate precursor B-cell acute lymphoblastic leukaemia.

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.

Using genome-wide bisulfite sequencing of acute lymphoblastic leukemia subtypes, cell lines and healthy cells, Hetzel et. al. find that unlike most cancers, ALL has a highly methylated genome, which points to a distinct mode of epigenome regulation in this cancer type.