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Notch1 is frequently activated promoting T-cell acute lymphoblastic leukaemia (T-ALL). Here, the authors show that Notch1 induces oxidative phosphorylation dependency in T-ALL and synergism when inhibiting both mitochondrial complex I and glutaminolysis in preclinical murine and human xenograft models.

Notch signaling has a crucial role in T cell acute lymphoblastic leukemia (T-ALL), but γ-secretase inhibitors (GSIs), which block the Notch pathway, cause intestinal toxicity that limits their use. Adolfo Ferrando and his colleagues now report that glucocorticoids can reverse the gut toxicity of GSIs, and GSIs can restore sensitivity of T-ALL cells to glucocorticoids, suggesting that this combination may have clinical utility in T-ALL and other diseases (pages 20–21).

Adolfo Ferrando and colleagues identify frequent inactivating mutations and deletions in the X chromosome gene PHF6 in T-cell acute lymphoblastic leukemia. PHF6 mutations are found almost exclusively in males and are associated with leukemias driven by aberrant expression of TLX1 and TLX3.

Adolfo Ferrando and colleagues report the exome sequencing of peripheral T cell lymphomas. They identified recurrent mutations in RHOA, TET2, DNMT3A, IDH2, FYN, ATM, B2M and CD58.

Teresa Palomero, Adolfo Ferrando, Raul Rabadan and colleagues report the results of an exome sequencing study of cutaneous T cell lymphoma (CTCL). They identify highly recurrent chromosomal deletions along with a broad spectrum of somatic mutations in genes involved in epigenetic regulation and signaling.

The first BCL-X_L-degrading PROTAC achieves safer and more potent antitumor activity than dual BCL-X_L and BCL-2 inhibitor navitoclax because of reduced dose-limiting platelet toxicity and high target specificity.

Ferrando and colleagues identify FYN–TRAF3IP2 as a recurrent oncogenic gene fusion that promotes angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma not otherwise specified through the activation of NF-κB signaling.

Genetic inactivation of the plant homeodomain 6 gene (Phf6) counteracts transcriptional and epigenetic aging programs in the hematopoietic system and can reverse the decline of hematopoietic stem cell function associated with age.

A foundation model learns transcriptional regulatory syntax from chromatin accessibility and sequence data across a range of cell types to predict gene expression and transcription factor interactions, with generalizability to unseen cell types.

Ferrando and colleagues analyze matched diagnostic and relapsed acute lymphocytic leukemia by whole-genome sequencing, and perform in vitro genome-wide CRISPR screens, to examine alterations associated with chemotherapy resistance.

The authors apply reverse engineering of transcriptional networks to identify the main functional drivers of the pro-leukemic transcriptional activity of TLX1 and TLX3, transcription factors usually altered in T-ALL. The network analysis uncovers RUNX1 as a key mediator of the effects of TLX factors and, consistently, mutations in RUNX1 are found in human T-ALL.

Mutations in the cytosolic 5′-nucleotidase II gene accelerate the inactivation of chemotherapeutic nucleoside analogs in acute lymphoblastic leukemia (ALL)-promoting lymphoblasts. Increased nucleotide metabolism may therefore constitute an important resistance mechanism in chemotherapy-resilient ALL.

TINCR encodes a p53-regulated ubiquitin-like microprotein expressed in stratified epithelia. Tincr loss promotes UVB-induced skin carcinogenesis in mice and deletions and mutations in human squamous cell carcinoma support a tumor suppressor role.

A global network of researchers was formed to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity; this paper reports 13 genome-wide significant loci and potentially actionable mechanisms in response to infection.

No targeted therapy has been approved yet for the treatment of T cell acute lymphoblastic leukemia. Here the authors show that unbiased phosphoproteomic profiling can identify targetable kinases and guide the design of personalized combination treatments using kinase inhibitors.

Orienting cancer drug discovery to the patient requires relating the genetic features of tumors to acquired gene and pathway dependencies and identifying small-molecule therapeutics that target them.

Genomic studies often lack representation from diverse populations, limiting equitable insights. Here, the authors show that the BIG Initiative captures extensive genetic diversity and reveals ancestry-linked health disparities in a community-based Mid-South cohort.

Exome sequence data from 628,388 individuals was used to identify 24 risk loci in 40,208 carriers of clonal haematopoiesis of indeterminate potential and link them to other conditions including COVID-19, cardiovascular disease and cancer.

An irreversible small-molecule inhibitor of histone methyltransferase NSD1 is developed, which binds covalently to the C2062 residue in the catalytic SET domain and represses H3K36 dimethylation and target gene expression in leukemia cells.

Oncogenic NOTCH1 controls transcriptional activation of the heat shock response in T cell acute lymphoblastic leukemia and uncovers potential biomarkers of sensitivity to HSP90 inhibition.

The authors uncover new mutations in an enzyme from the purine synthesis pathway that cause resistance to leukemia therapy, and reveal a new mechanism by which they affect drug metabolism.

The 17–92 miRNA cluster promotes tumourigenesis although the identity of the specific miRNA responsible for this effect has been unclear. MiR-19 is sufficient to promote Notch induced T-cell associated leukaemia in vivo and a shRNA screen for genes that phenocopy miR-19 effects identifies PI3-K regulators as miR-19 target genes.

The oncogenic activation of TLX transcription factors demarcates a specific molecular subtype of T cell acute lymphoblastic leukemia (T-ALL). This study identifies aneuploidy induction as a molecular mechanism by which TLX1 transforms T cell progenitors and reveals new TLX1 transcriptional targets, including Bcl11b, a crucial factor in T cell progenitor differentiation and survival, and Chek1, a mitotic checkpoint regulator. The findings delineate the role of TLX1 in T-ALL initiation and maintenance.

T cell acute lymphoblastic leukemia (T-ALL) is an immature hematopoietic malignancy driven mainly by oncogenic activation of NOTCH1 signaling¹. In this study we report the presence of loss-of-function mutations and deletions of the EZH2 and SUZ12 genes, which encode crucial components of the Polycomb repressive complex 2 (PRC2)^2,3, in 25% of T-ALLs. To further study the role of PRC2 in T-ALL, we used NOTCH1-dependent mouse models of the disease, as well as human T-ALL samples, and combined locus-specific and global analysis of NOTCH1-driven epigenetic changes. These studies demonstrated that activation of NOTCH1 specifically induces loss of the repressive mark Lys27 trimethylation of histone 3 (H3K27me3)⁴ by antagonizing the activity of PRC2. These studies suggest a tumor suppressor role for PRC2 in human leukemia and suggest a hitherto unrecognized dynamic interplay between oncogenic NOTCH1 and PRC2 function for the regulation of gene expression and cell transformation.

A long-range MYC enhancer is duplicated in human T-ALL and is required for T cell development and NOTCH1-induced leukemogenesis.

In this Review, Ferrando and López-Otín discuss the role of clonal evolution in leukemia and propose that better understanding of the evolutionary biography of human leukemias and related blood cell malignancies may contribute to improve their clinical management.

Hematopoietic stem cells infrequently proliferate, but their self-renewal is essential. Aifantis and colleagues show regulation of c-Myc protein stability by the ubiquitin ligase Fbw7 controls the self-renewal and differentiation potential of these cells.

A dataset of coding variation, derived from exome sequencing of nearly one million individuals from a range of ancestries, provides insight into rare variants and could accelerate the discovery of disease-associated genes and advance precision medicine efforts.

RNA-binding proteins are involved in post-transcriptional regulation. Turner and co-workers show that these proteins are also critical in thymopoiesis.

Genomic approaches in more than 500 patients are used to extend the number of chronic lymphocytic leukaemia (CLL) driver alterations, and also identify novel recurrent mutations in non-coding regions, including an enhancer of PAX5 and the 3′ untranslated region of NOTCH1, which lead to aberrant splicing events, increased NOTCH1 protein stability and activity, and an adverse clinical outcome.

In NOTCH-induced T cell acute lymphoblastic leukemia, the resistance to anti-NOTCH therapy conferred by loss of the Pten tumor suppressor is linked to reversal of the effects of NOTCH inhibition on leukemic cell metabolism.

João Barata and colleagues identify somatic gain-of-function IL7R mutations in childhood T-cell acute lymphoblastic leukemia. The mutations result in constitutive receptor activation, implicating the IL-7R pathway as a potential therapeutic target in a subset of T-ALL cases.

Anterior Uveitis is a common inflammatory eye disease that can result in vision loss. Here, the authors perform GWAS and whole-exome analyses of Anterior Uveitis to identify the underlying genetics of HLA-B*27 positive and negative forms of the disease.

Genotype and exome sequencing of 150,000 participants and whole-genome sequencing of 9,950 selected individuals recruited into the Mexico City Prospective Study constitute a valuable, publicly available resource of non-European sequencing data.

In a recent study, Maciocia et al. develop a novel T cell receptor beta (TCRB) constant C1-chain-directed cellular immunotherapy for the treatment of T cell malignancies.

Stroke is a multifactorial disease influenced by genetic and environmental factors. Here, the authors apply exome-wide association analysis to find rare coding variants associated with stroke in a Pakistani cohort, finding a significant association of a variant in NOTCH3 that is highly enriched in South Asians.

An exome-wide association study of six smoking phenotypes in up to 749,459 individuals identifies associations of rare coding variants in CHRNB2 that may reduce the likelihood of smoking.

This Review discusses the increased understanding of the biology of T cell acute lymphoblastic leukaemia (T-ALL) and how this has translated into new prognostic biomarkers, improved animal models and the emergence of targeted therapies to combat this disease.

Mutations in the nucleotidase-encoding gene NT5C2 drive chemotherapy resistance in relapsed acute lymphoid leukaemia but the mutations also lead to a loss-of-fitness phenotype and to collateral drug sensitivity, which could be exploited for therapy.

Jan Cools and colleagues identify deletions in PTPN2 in T-cell acute lymphoblastic leukemia. Inactivation of PTPN2 leads to an increase in cell proliferation in mouse T-ALL cells.

T-cell acute lymphoblastic leukaemia (T-ALL) is a haematological malignancy with a poor prognosis and no available targeted therapies; now two histone H3 lysine 27 demethylases, JMJD3 and UTX, are shown to have contrasting roles in human T-ALL cells and a mouse model of the disease, and a small molecule demethylase inhibitor is found to inhibit the growth of T-ALL cell lines, introducing a potential therapeutic avenue for acute leukaemia.