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Cytotoxic chemotherapy rarely generates durable anti-tumor immune responses. Here the authors show that tumor microenvironment-derived IL-6 promotes resistance to doxorubicin by suppressing CD8 T cell anti-tumor immune responses in a preclinical model of B-cell acute lymphoblastic leukemia.

Cancer is often associated with mutant transcription factors (TFs) but their functional characterization is challenging. Here, the authors describe a recurrent mutation within TF IRF4 in human lymphomas and they show how it causes a complex switch in TF specificity and functionality.

Circulating microbiome has been very little studied for blood malignancies. Here, the authors show specific microbiome signatures in the blood are associated with different types of myeloid malignancies and specific genetic mutations.

Antibody pairs are made to act selectively on cells co-expressing two targets by engineering their Fc domains.

Resident microbiota contribute to HIV and EBV infection in a germ-free humanized mouse model.

A screen for compounds that may inhibit the growth of hematological malignancies reveals the specific dependence of some mantle cell lymphoma (MCL) cell lines on canonical or alternative NF-κB signaling. As also seen in patients, genetic alterations affecting alternative NF-κB signaling confer insensibility to ibrutinib, a compound that was recently approved for MCL treatment. This alternative signaling pathway underscores the need to tailor treatments to the specific driving pathways in each patient group.

Inhibition of the protein arginine methyltransferase PRMT5 has been suggested as a promising therapy for lymphoma. Here, the authors show that TP53 loss of function and MUSASHI-2 (MSI2) expression are biomarkers of resistance to PRMT5-targeted therapy in B-cell lymphoma. Moreover, combining PRMT5 inhibition with MSI2 or BCL-2 inhibitors blocks the translation of key drivers of lymphoma, c-MYC and BCL-2, inhibiting cell growth.

Immunoglobulin (Ig) rearrangement and translocation information are usually obtained by targeted sequencing of the respective loci. Here, the authors present the IgCaller algorithm, which extracts Ig heavy and light chain genetic properties from short-read whole-genome sequencing results to provide a feasible alternative to direct sequencing.

Tobacco smoke contains more than sixty carcinogens that bind and mutate DNA. Here, massively parallel sequencing technology is used to sequence a small-cell lung cancer cell line, exploring the mutational burden associated with tobacco smoking. Multiple mutation signatures from the cocktail of carcinogens in tobacco smoke are found, as well as evidence of transcription-coupled repair and another, more general, expression-linked repair pathway.

Gottlieb and colleagues show that stearoyl-CoA desaturase promotes metabolic adaptation of acute lymphoblastic leukemia cells to the central nervous system microenvironment, revealing a potential site-specific metabolic vulnerability of this disease.

A approach termed ‘receptor inhibition by phosphatase recruitment’ is described for attenuating both tonic and ligand-activated cell-surface receptor signalling.

In cancer, global DNA methylation loss and CpG island hypermethylation are commonly observed. Here, in breast cancer the authors find that hyper-variability of partially methylated domains is the prime source of DNA methylation variation and that these domains fuel CpG island hypermethylation.

Here, the authors design a multiplex serology platform to quantitatively measure antibodies against 20 infectious agents in UK Biobank participants and confirm associations of antibody responses with sociodemographic characteristics, HLA genetic variants, and disease outcomes.

A genomic, transcriptomic and epigenomic analysis of chronic lymphocytic leukemia identifies genetic drivers and molecular subtypes associated with clinical outcomes.

Plasmablastic lymphoma (PBL) is an aggressive lymphoma subtype characterized by poor prognosis but the molecular knowledge of the disease is limited. Here, the authors perform whole exome sequencing and copy number determination of primary samples highlighting IRF4 and JAK-STAT pathways as therapeutic targets for PBL.

UNC5B is a Netrin-1 receptor expressed in endothelial cells that in the absence of ligand induces apoptosis. Here the authors identify an UNC5B splicing isoform that is insensitive to the pro-survival ligand Netrin-1 and is required for apoptosis-dependent blood vessel development.

Multiple myeloma, a malignancy of plasma cells, remains incurable and is poorly understood. Using next-generation sequencing of several multiple myeloma genomes reveals that this disease involves mutations of genes involved in protein translation, histone methylation and blood coagulation. The study suggests that BRAF inhibitors should be evaluated in multiple myeloma clinical trials.

A series of genome-wide and targeted CRISPR screens uncovered regulators of antibody–drug conjugate (ADC) toxicity. Depletion of sialic acids was found to enhance ADC lysosomal delivery, in part by reducing ADC recycling.

A comparative transcriptional analysis identifies human HLA-DR as a factor that mediates entry of bat influenza A-like H17-pseudotyped viral particles into mammalian cells.

Cancer cells have previously been shown to be addicted to glutamine and glutaminase enzyme activity. Here, the authors show that overexpression of the JUN proto-oncogene in breast cancer cells regulates glutaminaseexpression and is sufficient to confer sensitivity to glutaminase-targeted therapy.

Mapping enhancer regulation across human cell types and tissues illuminates genome function and provides a resource to connect risk variants for common diseases to their molecular and cellular functions.

The genomic characterisation of nasopharyngeal carcinoma (NPC) remains crucial. Here, the authors perform whole-genome sequencing for 70 NPCs with EBV gene expression, report the somatic alterations and EBV-mediated effects converging on NF-κB activation and immune escape and identify targetable homozygous MTAP deletions.

Chickens acutely exposed to polystyrene nanoparticles are less efficient at absorbing iron across the epithelial cells of their intestines than chickens chronically exposed and those that are not exposed at all.

Gastric cancer has two distinct morphologic subtypes, intestinal and diffuse, that differ in genetic composition and clinical manifestation. Here, the authors carry out whole-genome sequencing of diffuse and intestinal gastric cancer samples and characterize the mutational landscape of these different subtypes.

The ribonucleotide reductase large subunit of the Epstein–Barr virus, BORF2, inhibits the DNA cytosine deaminase activity of the host restriction factor APOBEC3B and sequesters it in perinuclear and cytoplasmic bodies, thus preserving viral genome integrity during lytic reactivation.

Identifying the cellular targets of small molecules remains a central challenge of chemical biology. The application of an RNAi-based functional genomics approach permitted the clustering of drugs with related targets by 'shRNA signatures', which served as a basis set to assign modes of action to compounds with unknown targets.

The Wnt pathway is one of the core de-regulated pathways in chronic lymphocytic leukaemia (CLL) and is activated in only a subset of patients; however, no universal drivers of the disease have been identified. Here the authors show that Notch2 and β-catenin pathways are the main drivers of the pro-survival bidirectional crosstalk between stromal cells and leukemic cells.

Principal component analysis is a multivariate statistical method that reduces a large number of variables into fewer variables, called principal components. This Primer describes how the method can be used for data analysis, explaining the mathematical background, analytical workflows, how to interpret a biplot and variants of the method.

Lape et al. use electronic health records and a discovery-replication cohort study design to investigate links between common pathogens and non-communicable diseases. Evidence is found for over 200 associations, such as a role for human cytomegalovirus in ulcerative colitis.

An in vivo transposon screen in a pancreatic cancer model identifies frequent inactivation of Usp9x; deletion of Usp9x cooperates with Kras^G12D to accelerate rapidly pancreatic tumorigenesis in mice, validating their genetic interaction.