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MraZ, a conserved transcription factor, controls bacterial cell division by binding the dcw operon promoter. Here, the authors present cryo-EM structures of M.genitalium MraZ with its 4-box promoter, revealing its DNA-binding mechanism

Clonal haematopoiesis of indeterminate potential is driven by somatic mutations in hematopoietic stem/progenitor cells and may progress to myelodysplastic syndromes (MDS). Here authors show that the two conditions share a similar pattern of bone marrow remodeling, characterized by the emergence of inflammatory mesenchymal stromal cells and IFN-responsive T cells, reinforcing their shared etio-pathology.

Age is a risk factor for SARS-CoV-2 infection and severe disease. Here the authors perform DNA methylation analyses in whole blood from COVID-19 patients using established epigenetic clocks and telomere length estimators, and describing correlations between epigenetic aging and the risk of SARS-CoV-2 infection and severe disease.

In JAK2V617F mutant myeloproliferative neoplasms (MPN), inflammation impacts clinical outcomes. This study uncovers that the NLRP3 inflammasome drives thrombocytosis, granulocytosis, HSPC expansion, splenomegaly, and bone marrow fibrosis in MPN

Gámez-García et al. show that the deacetylase SIRT7 modulates the acetylation of Pax5 and its ability to repress alternate lineage programs and promote B cell differentiation and commitment in B cell progenitor cells.

Scourzic et al. show that germinal centre B cells display an enhanced ability to reprogram to induced pluripotent stem cells compared to mature B cells. This ability indicates their higher plasticity level and is T follicular helper cell-dependent.

GATA2 deficiency is one of the major causes of hereditary pediatric myelodysplastic neoplasms (MDS). Using iPSC-based models, this work recapitulates stepwise mutational trajectories in GATA2-related MDS and reveals their impact on myeloid differentiation.

HIV remission of more than 6 years was achieved in a patient with functional viral co-receptors after CCR5 wild-type/Δ32 allogeneic stem cell transplantation, providing evidence of other mechanisms that can be harnessed to attain long-term remission.

Chronic care manages long-term, progressive conditions, while acute care handles short-term ones. Here, authors show chronic conditions account for most of the global health burden, with 68% of DALYs and 93% of YLDs attributed to chronic care needs.

A longitudinal multiomics analysis of a patient with multiple myeloma who developed peripheral T cell lymphoma after treatment with anti-BCMA CAR T cells and a GPRC5D-directed bispecific antibody reveals that two mutated CAR⁺CD8⁺ T cell clones were probably drivers of the neoplasm.

Azacitidine (AZA) treatment is used for patients with myelodysplasias that cannot undergo bone marrow transplantation; however, AZA treatment is only partially effective. Here the authors show synergy of AZA with compounds inhibiting the chromatin regulators CBP and p300, which is mediated by the RNA-dependent functions of AZA affecting protein translation.

Ewing sarcoma (ES) is characterized by EWSR1/ETS gene rearrangements with unknown cellular origin. Here, authors show that expressing the EWS::FLI1 oncogene in human embryonic mesenchymal stem cells induces an Ewing sarcoma-like transcriptome and forms tumors in mice.

CEBPA is frequently mutated in acute myeloid leukemia (AML), but the transcriptional impact of the AML-associated isoform remains unclear. Here, the authors show that CEBPA-mutant cells have reduced inflammatory expression and higher sensitivity to ER stress due to impaired function of AP1 factors.

In 1,088 pregnant individuals, assessment of abnormal serum angiogenic factors is demonstrated to be noninferior to the standard clinical approach based on estimated fetal weight and Doppler percentiles for the identification of fetuses at a higher risk of neonatal acidosis or Cesarean delivery, thus offering a beneficial option in settings where Doppler or experienced sonographers are not readily available.

Engineered polypeptide cleavage in vivo demonstrates that the loss of titin tension induces severe muscle atrophy.

Infant KMT2A-rearranged acute lymphoblastic leukemia is associated with poor overall survival rates. Here, the authors use WGS and WES of 36 relapsed KMT2A-rearranged ALL and AML patients and find alterations in drug response genes in ALL, which may correspond with relapse time. Longitudinal analyses of >250 samples could track residual leukemia cells, clonal drug responses, and the upcoming relapse.

In Myeloiddysplastic syndromes, CEBPA mutations are linked to disease progression and AML. Here, the authors use somatic reprogramming and genome editing to generate isogenic cell lines from an MDS patient, identifying CEBPA bZIP domain disruption as causative for disease progression.

Interact-omics, a high-throughput cytometry-based framework, resolves the cellular interaction landscape.

The DNAJB1-PRKACA fusion transcript is the oncogenic driver in fibrolamellar hepatocellular carcinoma, a lethal disease with limited therapeutic options. Here, the authors identify the DNAJB1-PRKACA protein as a source for immunogenic neoepitopes and a potential target of T cell-based immunotherapy.

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.

Most genetic studies have been done on European cohorts, which affects the efficacy of polygenic risk scores in non-European populations. Here, the authors demonstrate that a colorectal cancer PRS including Asian and European ancestries has improved performance over the European-centric PRS across racial and ethnic groups.

Chimeric antigen receptor T (CAR-T) cells represent a breakthrough in the treatment of haematopoietic malignancies, however, in solid tumours this form of immune therapy is hampered by the scarcity of suitable targets showing high level tumour-restricted expression. Here authors generate CAR-T cells that target an osteosarcoma-specific isoform of alkaline phosphatase and show efficacy in orthotopic animal models while sparing healthy tissues.

During tuberculosis infection there is formation of a TB containing lesion within the lungs. Here the authors characterise the cellular and molecular features of human TB lesions and demonstrate associations with clinical severity and treatment efficacy.

By deciphering the molecular fingerprint of cells treated with host-directed therapies targeting protein translation, the authors identified a rational approach to select for broad-spectrum antivirals with potential to counteract future pandemic viruses.

Kim and colleagues perform a phase 2 clinical trial (ELM-2) of odronextamab monotherapy in patients with relapsed/refractory diffuse large B cell lymphoma and report on the primary analyses of the efficacy and safety profile.

A genome-wide study by the Long COVID Host Genetics Initiative identifies an association between the FOXP4 locus and long COVID, implicating altered lung function in its pathophysiology.

DNA transactions promote torsional constraints that pose inherent risks to genome integrity. Here the authors identify the macro-histone splice variant macroH2A1.1 as an epigenetic modulator of topoisomerase 1-associated genome maintenance. MacroH2A1.1 expression determines sensitivity to TOP1 poisons and may present a cancer vulnerability.

MacroH2A histone variants originated before the split of fungi and animals. ADP-ribose binding is an ancestral feature of their macrodomains and is linked to the compartmental regulation of NAD metabolism. This function was selected for during the evolution of metazoans.

Mesenchymal stromal cells (MSCs) have been shown to support multiple myeloma (MM) development. Here, MSCs isolated from the bone marrow of MM patients are shown to have altered DNA methylation patterns and a methyltransferase inhibitor reverts MM-associated bone loss and reduces tumour burden in MM murine models.

Here the authors uncover p53’s role as the master regulator of spatio-temporal genome organization. p53 controls the expression of 340 distal genes through newly formed and pre-existing loops between p53-bound enhancers and promoters.

Immune-checkpoint inhibitors are revolutionizing the treatment of many types of solid cancer. Expression of the inhibitory immune-checkpoint proteins programmed cell-death 1 (PD-1) and its ligands (PD-L1 and PD-L2) are frequently detected in haematological malignancies, and agents targeting these proteins have activity in such diseases, notably Hodgkin lymphoma. Herein, the current evidence supporting the roles of PD-1–PD-L1 blockade in the treatment of various B-cell malignancies is reviewed.

Patient-derived xenografts (PDX) could contribute to understanding how colorectal cancer (CRC) responds to targeted therapies like cetuximab. Here, the authors characterise the response to cetuximab in 231 CRC PDXs using multiomics and develop an integrative ensemble classifier - CeSta - to predict sensitivity to cetuximab.

Primary cilia are cell organelles disrupted in developmental diseases and cancer. Here, the authors identify cilia regulators that generate a specific cilia membrane lipid, which may help to better understand diseases caused by mutations in PI3-kinase subunits.

Endothelial cells in white adipose tissue are shown to produce polyamines, which regulate adipocyte lipolysis, thus demonstrating how local angiocrine signals contribute to healthy adipose tissue homeostasis.

Multiomic factor analysis of blood multiomic data, including single-cell transcriptomics, for individuals with either acute or chronic coronary syndrome identifies immune cell signatures that correlate with treatment outcomes.

In lung cancer, relatively few germline mutations are known to impact risk. Here the authors looked at rare variants in 39,146 individuals and find novel germline mutations associated with risk, as well as implicating ATM and a new candidate gene for lung cancer risk.

Here, the authors investigate the proteome trajectory of human iPSCs differentiating into hepatic stellate cells (diHSCs) and identify RORA as a key transcription factor that governs metabolic reprogramming essential for diHSCs’ commitment, identity, and quiescent phenotype.

The authors reconstruct high fidelity networks of protein-protein interactions between promoters and enhancers in prostate cancer and demonstrate the potential of such an analytical framework to obtain actionable insights into the disease and potential therapeutic targets.

Zeiser and colleagues show that CAR T cell therapy results in upregulation of the TGFβ-activated kinase-1 (TAK1)–NF-κB–p38 MAPK pathway in microglia, causing neurocognitive defects, and find that TAK1 inhibition can reduce immune effector cell-associated neurotoxicity syndrome.