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Multi-modality single-cell sequencing determines genotype, transcriptome and methylome information in cells from individuals with DNMT3A R882 mutated clonal hematopoiesis, allowing for the comparison of mutant and wild-type cells from the same individuals.

One way of discovering genes with key roles in cancer development is to identify genomic regions that are frequently altered in human cancers. Here, high-resolution analyses of somatic copy-number alterations (SCNAs) in numerous cancer specimens provide an overview of regions of focal SCNA that are altered at significant frequency across several cancer types. An oncogenic function is also found for the anti-apoptosis genes MCL1 and BCL2L1, which reside in amplified genome regions in many cancers.

The myeloproliferative disorders (MPD) polycythaemia vera (PV), essential thombocythaemia (ET), and primary myelofibrosis (PMF) are clonal disorders of multipotent haematopoietic progenitors, and most patients with these diseases acquire a single point mutation in the cytoplasmic tyrosine kinase JAK2 (JAK2V617F). What are the implications of these findings for MPD?

Unexpectedly, new data show that clonal hematopoiesis is associated with protection from Alzheimer’s disease; it is imperative that future studies unravel the complex tissue–disease contexts in which clonal hematopoiesis arises and contributes to aging-associated diseases.

Mapping of the clonal structure of bone marrow cells in patients with acute myeloid leukemia treated with the IDH2 inhibitor enasidenib reveals heterogeneity in the cellular differentiation response and in mechanisms of relapse.

The RNA binding protein MUSASHI-2 (MSI2) is a potential therapeutic target for acute myeloid leukemia. Here the authors identify a small molecule inhibitor of MSI2 and characterize its effects in a murine leukemia model.

The loss of the TP53 gene is often involved in the development of human cancer; here, the deletion of other genes in the vicinity is shown also to contribute to cancer progression in a mouse model.

The response to infectious and inflammatory challenges differs among people but the reasons for this are poorly understood. Here the authors explore the impact of variables such as age, sex, and the capacity for controlling inflammation and maintaining immunocompetence, linking this capacity to favourable health outcomes and lifespan.

A CRISPR–CAS9 screen, analysis of patient data, and functional in vivo and in vitro experiments identify a critical role for ARID1A in determining breast luminal cell identity and endocrine therapeutic response in estrogen-receptor-positive breast cancer.

Melnick and colleagues show that the cohesin complex exhibits dose-dependent regulation of chromatin remodeling that accompanies the transition of germinal center B cells to plasma cells, which is necessary to prevent lymphomagenesis.

Whole-genome sequencing analysis of individuals with primary immunodeficiency identifies new candidate disease-associated genes and shows how the interplay between genetic variants can explain the variable penetrance and complexity of the disease.

A new study demonstrates that dysregulation of proteostasis can be a transforming event in hematopoiesis that could prove to be therapeutically actionable for treatment of myeloproliferative neoplasms.

The complex microenvironmental signalling pathways that govern haematopoietic stem cell (HSC) activity remain poorly defined. Here, the authors identify endothelial NF-κB signalling as regulating regenerative HSC function, accelerating haematopoietic recovery following myelosuppressive injury in mice.

Preliminary results from the Beat AML umbrella trial demonstrates the feasibility and efficacy of applying prospective genomic profiling for matching newly diagnosed patients with AML with targeted therapies.

Michael Kharas and colleagues characterize the MSI2 protein interactome in leukemia cells and subsequently perform a functional screen identifying 24 genes required for leukemia in vivo. They focus on the RNA-binding protein SYNCRIP, showing that it regulates Hoxa9 and other transcripts involved in a myeloid leukemia stem cell program.

The mainly hematologic expression profile of phosphatidylinositol-3-kinase-γ (PI3Kγ) makes it an attractive therapeutic target. Recent work from three independent groups shows that inhibiting PI3Kγ impairs the metabolism and growth of acute myeloid leukemia cells — a finding that justifies further mechanistic and clinical exploration.

Genome-wide methylome sequencing of serial samples obtained from patients with acute myeloid leukemia reveals that epigenetic alleles and genetic alleles follow independent courses during disease evolution.

The inhibitor PU-H71 preferentially targets tumor-enriched Hsp90 complexes. Affinity purification using PU-H71 reveals cancer-specific protein networks in chronic myeloid leukemia and that the abundance of tumor-specific Hsp90 clients in cells can predict sensitivity to Hsp90 inhibitors.

In 2008, the first comprehensive sequence of a cancer genome was reported, ushering in a new era of molecular diagnostic, prognostic and therapeutic advances informed by an essential framework to understand cancer’s complexities.

Nan Wang and colleagues uncover a new function for HDL that may contribute to its anti-atherosclerotic effects. In the bone marrow, HDL removes cholesterol from megakaryocyte progenitor cells in a process requiring the cholesterol transporter ABCG4, thereby dampening megakaryocyte and platelet production.

Ageing is associated with an increased risk of cardiovascular disease caused by the rupture of inflamed cholesterol plaques in arteries. It emerges that this might be partly due to genetic mutations that cause cancerous changes in white blood cells.

Although genome-wide analyses have identified somatic alterations contributing to the pathogenesis of pediatric acute lymphoblastic leukemia (ALL), few studies have identified germline variants conferring risk of this disease. Two reports now provide the first genome-wide glimpse into the role of inherited alleles in ALL pathogenesis.

An inhibitor of Aurora kinase promotes megakaryocytic differentiation of cells from patients with primary myelofibrosis and shows antifibrotic effects in mouse models of this disease.

Chaperomes are dynamic assemblies of proteins that regulate cellular homeostasis but specific cellular stresses remodel chaperome components into a stable chaperome network called the epichaperome, which might offer a new cancer target.

Ramos et al. report a crucial role for macrophages in erythroblast development in mice. Under conditions that induce new red blood cell formation, macrophage depletion impaired red blood cell recovery. Conversely, macrophage depletion normalized red blood cell counts in mouse models of polycythemia vera and ®-thalassemia, pointing to a potential new therapeutic strategy for these diseases. Findings similar to these are reported in an accompanying paper by Chow et al.

An international consortium reports the genomic sequence for ten Drosophila species, and compares them to two other previously published Drosophila species. These data are invaluable for drawing evolutionary conclusions across an entire phylogeny of species at once.

This Perspective discusses how the Somatic Cell Genome Editing Consortium aims to accelerate the implementation of safe and effective genome-editing therapies in the clinic.

The COVID-19 pandemic has broadly impacted biomedical research and health care. Here we discuss current challenges for the cancer research community as they apply to early career investigators (ECIs). We propose a series of collaborative initiatives aimed to sustain ECIs and preserve and accelerate the ability to innovate with long-lasting impact.

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.

Acute myeloid leukaemia (AML) is a heterogeneous disease that is typically associated with a very poor prognosis; however, cytogenetic and molecular abnormalities that characterize different forms of AML have been used to better prognosticate patients and inform treatment strategies, which might enable better outcomes to be achieved. Moreover, in the era of next-generation sequencing and molecularly targeted therapy, genetic profiling of patients with AML could open new avenues of treatment. Herein, the authors discuss the evidence-base for integrating mutational data into treatment decisions for patients with AML, and propose novel therapeutic algorithms aimed at improving outcomes of this dismal disease by promoting clinical research.

The genome of the grey short-tailed opossum Monodelphis domestica has been sequenced and analyzed, giving a first peek at a marsupial's genetic code. Of particular interest are the genetics of the immune system, which has been studied as a model for humans, and of the X chromosome for historical reasons.

Cancer-associated IDH mutants that produce 2-hydroxyglutarate are shown to prevent the histone demethylation that is required for lineage-specific progenitor cells to differentiate into terminally differentiated cells.

The significance of epigenomic aberrations in cancer development has been underscored by the discovery of mutations in key chromatin modifiers, most notably in hematological malignancies. A new study of pediatric acute lymphoblastic leukemia (ALL) demonstrates the usefulness of mapping global epigenetic signatures and applying these data in a framework to identify and characterize underlying somatic genetic alterations in human cancers.

William Carroll and colleagues report the identification of mutations in NT5C2, encoding cytosolic 5′-nucleotidase II, which are specific for relapsed childhood acute lymphoblastic leukemia. The mutations confer increased enzymatic activity and resistance to treatment with nucleoside analog therapies in vitro.

Combined analysis of proton-proton collision data from the Large Hadron Collider at CERN by the CMS and LHCb collaborations leads to the observation of the extremely rare decay of the strange B meson into muons; the result is compatible with the standard model of particle physics, and does not show any signs of new physics, such as supersymmetry.

Analyses of transcriptomes from patients with acute myeloid leukaemia identified frequently co-occurring mutations of IDH2 and SRSF2, which functional analyses showed to have distinct and coordinated leukaemogenic effects on the epigenome and RNA splicing.

BAP1 regulation of EZH2 provides therapeutic opportunities in cancer.

Single-cell analysis of mouse hematopoietic stem cells shows that mutations in DNA methylation genes change the frequencies of erythroid versus myelomonocytic progenitors, owing to differential CpG enrichment in transcription factor binding motifs.

Peter Donnelly and colleagues report a genome-wide association study for Barrett's esophagus, a common premalignant condition associated with stomach acid reflux and predisposing to esophageal adenocarcinoma. They identify two loci associated with susceptibility to Barrett's esophagus.

Mutation of isocitrate dehydrogenase 1 (IDH1) is shown to induce DNA hypermethylation and to remodel the epigenome to resemble that of gliomas with the CpG island methylator phenotype.

The Tet2 enzyme, which catalyses de novo hydroxymethylation of DNA, is shown here to act as a transcriptional repressor by recruiting the histone deacetylase Hdac2 to the Il6 promoter in the course of resolution of the LPS-induced inflammatory response.

Wei Zheng and colleagues report genome-wide analyses in east Asians and identify three new loci associated with colorectal cancer risk.

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.