Clonal haematopoiesis, or CH, arises when somatic mutations in haematopoietic stem cells allow them to outcompete their neighbours and produce expanded populations of mutant blood cells detectable in the peripheral circulation. The condition is remarkably common, present in an estimated 10 to 20 percent of people over the age of 65, and by mid-century the global population over 65 is projected to double, placing hundreds of millions of people at risk of CH-associated complications. Mutations in DNMT3A and TET2 together account for roughly 70 percent of all CH variants, and both have been linked to heightened inflammatory responses in myeloid cells, as well as increased risk of haematologic malignancies and cardiovascular disease. Yet the cell-intrinsic mechanisms connecting these mutations to inflammatory signalling have remained incompletely understood, and clinicians have long struggled to explain why individuals carrying the same mutation can show such different clinical outcomes.

The research team hypothesised that retrotransposable elements, or RTEs, might provide the missing mechanistic link. These genomic parasites, including long interspersed nuclear elements (LINEs), short interspersed nuclear elements (SINEs), and long terminal repeat (LTR) elements also known as human endogenous retroviruses, are normally silenced by DNA methylation and repressive histone modifications. When that silencing breaks down, RTEs can produce RNA and even DNA copies that the cell mistakes for viral invaders, activating innate immune sensors such as cGAS and triggering type-I interferon responses. RTE derepression is increasingly recognised as a hallmark of ageing and has been implicated as a causative factor in cellular senescence, making it a natural suspect in a condition defined by age, mutation, and inflammation.

To test the hypothesis, the researchers analysed peripheral blood mononuclear cell samples from 56 individuals with clonal haematopoiesis and 12 non-CH controls, drawn from a larger population study of 738 otherwise healthy adults over 50 recruited through elective hip replacement surgery at King’s College Hospital in London and The Robert Jones and Agnes Hunt Orthopaedic Hospital in Oswestry. Genomic DNA was sequenced with a customised myeloid panel achieving deep coverage through error-corrected duplex consensus reads, while RNA sequencing without poly(A) selection captured both gene and repetitive element expression, averaging 65.1 million paired-end reads per sample. Participants were stratified into five groups: DNMT3A-mutant high variant allele frequency (VAF above 10 percent, n = 10), DNMT3A-mutant low VAF (n = 30), DNMT3A/TET2 double-mutant (n = 9), TET2-mutant (n = 7), and non-CH controls (n = 12).

The results were unambiguous for the largest expanded clones. High-VAF DNMT3A-mutant clones exhibited widespread derepression of retrotransposable elements, dominated by the LINE:L1 and LTR:ERV1/ERVL families, which are typically repressed by DNA methylation. This pattern fits neatly with prior work showing that DNMT3A loss disrupts de novo methylation and permits repetitive element reactivation in haematopoietic and embryonic stem cells. Interestingly, the high-VAF DNMT3A group was not uniform: the team identified two distinct subgroups, one with markedly elevated RTE expression and another resembling controls, revealing substantial heterogeneity within the same mutation class. The position of the mutation within the protein appeared to matter, with variants affecting the PWWP domain exclusively associated with the RTE-high phenotype, and within the methyltransferase domain most high-VAF mutations showing elevated RTE expression except the recurrent R882H hotspot, which clustered in the RTE-low group. The authors caution that with only ten high-VAF cases these observations require validation in larger cohorts, but they suggest that different DNMT3A mutations may not be biologically equivalent.

Functionally, the RTE-high DNMT3A clones looked dramatically different from their RTE-low counterparts. Gene set enrichment analysis showed that high-VAF DNMT3A clones with elevated RTE expression were enriched for inflammatory signalling pathways, including TNF-alpha/NF-kappaB signalling and broad inflammatory response programmes. At the effector level, these clones expressed significantly higher levels of TNF and the alarmin S100A9, and showed upregulation of multiple interferon regulatory genes, including ISG15, IFI44, IFIT1, IFIT2, and IFIT3, a signature consistent with RTE-derived nucleic acids activating cytosolic sensors and driving type-I interferon responses. The researchers also observed enrichment of pathways involving the Human Silencing Hub (HUSH) and Sirtuin 1 (SIRT1), which they interpret as possible compensatory attempts by alternative epigenetic regulators, including HUSH, Polycomb Repressive Complex 2, and SIRT1, to preserve transcriptional repression in the face of failing DNMT3A-mediated methylation, a coordinated but ultimately failing cellular response rather than random transcriptional noise.

TET2-mutant clones told a completely different story. Far from derepressing retroelements, TET2-mutant haematopoiesis showed a trend towards reduced RTE expression relative to controls, and no significant associations between RTE activity and any of four curated inflammatory and ageing signatures: interferon regulatory genes, TNF-NF-kappaB, senescence, and the senescence-associated secretory phenotype (SASP). Instead, pathway analysis revealed that TET2-mutant clones were enriched for oxidative phosphorylation, reactive oxygen species signalling, and mechanistic target of rapamycin complex 1 (mTORC1) signalling, pointing to a metabolically driven, redox-associated inflammatory phenotype rather than a retroelement-driven one. This aligns with recent publications implicating metabolic and inflammasome pathways, rather than transposable element activation, in TET2-mutant inflammation. In regression analyses, RTE family expression was significantly and positively associated with all four signature scores in DNMT3A high-VAF cases, showed more selective associations with interferon and senescence programmes in low-VAF DNMT3A cases, and showed no significant associations in TET2-mutant cases.

The findings held up under independent scrutiny. Single-cell TARGET-seq data from a separate study, covering five DNMT3A-mutant and three TET2-mutant samples, showed that DNMT3A-mutant cases contained more upregulated RTE subfamilies across individual haematopoietic lineages, with the erythroid and megakaryocyte compartments showing the strongest enrichment and ERV1, ERVL, ERVL-MaLR, and L1 families contributing most. An external validation cohort of 92 healthy middle-aged and older adults from a publicly available RNA-seq dataset, in which RNAVAR mutation calling identified seven DNMT3A and six TET2 high-VAF cases, reproduced the core pattern: retroelement expression correlated significantly with interferon, TNF-NF-kappaB, and senescence signatures in DNMT3A high-VAF clones but not in TET2-mutant cases. Double-mutant clones carrying both mutations occupied an intermediate position, with RTE levels higher than TET2-mutants but lower than DNMT3A high-VAF clones, and attenuated TNF-NF-kappaB and interferon programmes, hinting at non-redundant and possibly antagonistic roles for the two epigenetic regulators.

The study has limitations the authors acknowledge candidly. Bulk RNA sequencing of peripheral blood mononuclear cells can be influenced by differences in cellular composition, and although the TARGET-seq analyses supported cell-intrinsic differences in RTE regulation, the small single-cell cohort cannot fully exclude compositional effects. The number of high-VAF cases remains modest, and, critically, the data demonstrate an association between RTE derepression and inflammatory pathway activation rather than a proven causal relationship, since both could arise as parallel consequences of DNMT3A-associated epigenetic dysregulation. Recurrent co-occurring CHIP mutations were found in only 10 percent of DNMT3A-mutant cases and showed no enrichment in the RTE-high or high-VAF groups, making co-mutations an unlikely explanation for the observed heterogeneity.

Even so, the implications are considerable. By showing that inflammation in clonal haematopoiesis is mutation-specific, with retrotransposon reactivation powering the inflammatory programme of DNMT3A-mutant clones while metabolic and redox dysregulation drive TET2-mutant inflammation, the study lays the groundwork for mutation-specific biomarkers and therapies. If future functional and preclinical studies confirm that modulating RTE activity can dampen the inflammatory phenotype of DNMT3A-mutant clonal haematopoiesis, interventions could one day be tailored to the specific molecular mechanism behind each patient’s mutated clone, replacing a one-size-fits-all approach with precision medicine for age-related blood disorders and, potentially, the cardiovascular and neurodegenerative diseases that travel with them.

Subject of Research: Mutation-specific retrotransposable element derepression and inflammatory signalling in DNMT3A- and TET2-mutant clonal haematopoiesis

Article Title: Retrotransposable element derepression distinguishes DNMT3A-mutant from TET2-mutant clonal haematopoiesis

Article References: Hasan, M., Durandeau, S., Thompson, I. R., Roussotte, H., Tsai, Y.-T., Seymen, N., Gerlevik, S., Bianchini, N., Alishah, K., Albuquerque, M. M., Lewis, J., Bonganay, L., Jakobsen, N. A., Zeisig, B., Irshad, S., Vyas, P., So, E. C. W., Iacoangeli, A., Zheng, X., … Karimi, M. M. (2026). Retrotransposable element derepression distinguishes DNMT3A-mutant from TET2-mutant clonal haematopoiesis. GeroScience. https://doi.org/10.1007/s11357-026-02510-6

Image Credits: AI Generated

DOI: 10.1007/s11357-026-02510-6

Keywords: clonal haematopoiesis, DNMT3A, TET2, retrotransposable elements, LINE-1, endogenous retroviruses, inflammation, ageing, DNA methylation, interferon signalling, senescence, haematopoietic stem cells

The research team took advantage of whole blood transcriptomics, a technique that measures the activity of thousands of genes simultaneously in circulating immune cells. Rather than examining individual molecules in isolation, transcriptomics captures the coordinated behaviour of the entire immune system at a single moment, revealing which defensive programmes have been switched on, which have been silenced, and how the composition of the blood cell population itself has shifted in response to infection. This systems-level view is particularly valuable in paediatric respiratory disease, where clinical symptoms overlap considerably between viral and bacterial pathogens and where the biological drivers of severity remain poorly understood.

The study drew on children enrolled in the Drakenstein Child Health Study and the Pneumonia in South Africa Programme, longitudinal research platforms based in South Africa that have followed children in communities where the burden of lower respiratory tract illness is among the highest in the world. The investigators compared whole blood transcriptomes from 127 healthy children with those from 71 children who had mild or asymptomatic SARS-CoV-2 infection, 41 children hospitalised with severe SARS-CoV-2 disease, 47 children hospitalised with respiratory syncytial virus-associated lower respiratory tract illness, and 47 children with pulmonary tuberculosis. This design allowed the researchers to distinguish a general response to respiratory illness from pathogen-specific signatures and, crucially, to identify the molecular features that separate mild from severe COVID-19 in children.

The scale of the transcriptional differences was striking. The team identified more than 5,000 differentially expressed genes across the disease groups, all passing a stringent statistical threshold that controls the false discovery rate at below 5 percent. In children with severe SARS-CoV-2, standout genes included OLFM4, IFI27, CBX7, IGF2BP3 and OTOF. In RSV-associated lower respiratory tract illness, the most distinctive genes were IFI27, OTOF, SIGLEC1, IFI44L and USP18, several of which are well-known markers of interferon-driven antiviral activity. Pulmonary tuberculosis produced its own signature, dominated by MMP8, LTF, IGF2BP3, GPR84, CD177, C1QC and DEFA4, genes associated with neutrophil activation, granule release and the complement cascade, consistent with the intense myeloid inflammation that characterises tuberculous lung disease.

Pathway analysis of the severe COVID-19 group, compared with healthy uninfected children, revealed enrichment of neutrophil degranulation and interferon gamma signalling, alongside overexpression of genes encoding ribosomal proteins and a measurable depletion of general immune response programmes. Neutrophil degranulation refers to the release of toxic granule contents by these frontline white blood cells, a process that helps destroy pathogens but can also damage surrounding tissue when excessive. Interferon gamma, meanwhile, is a cytokine that orchestrates macrophage activation and antiviral defence. The combination of a strong neutrophil-driven inflammatory programme with signs of broader immune dysregulation echoes patterns previously documented in adults with severe COVID-19, and the authors note that severe disease in children exhibits a cellular response similar to that reported in adult patients.

To move beyond lists of individual genes, the researchers applied Weighted Gene Co-expression Network Analysis, a computational method that clusters genes into modules based on correlated patterns of expression across samples. Rather than treating each transcript as an independent variable, WGCNA identifies groups of genes that rise and fall together, which often reflects shared biological regulation. The analysis uncovered 10 such correlated gene modules that were shared across the different lower respiratory tract infections, suggesting that despite the distinct causative pathogens, the underlying response mechanisms in the blood draw on a common repertoire of immune programmes. This convergence helps explain why children with different infections can present with similar clinical pictures while still carrying pathogen-specific fingerprints detectable at the transcriptomic level.

The team also performed cellular decomposition analysis, a computational approach that infers the relative abundance of different immune cell types in whole blood from their gene expression patterns, avoiding the need for physical cell sorting. The results were sobering. Compared with healthy children, severe SARS-CoV-2 was associated with the depletion of 22 distinct cell populations, RSV-associated illness with 16, and pulmonary tuberculosis with 21. Depletion of circulating lymphocyte subsets is a recognised feature of severe respiratory viral infections and is thought to reflect both redistribution of cells to infected tissues and infection-induced cell death. The breadth of this depletion in severe paediatric COVID-19 underscores how profoundly the cellular architecture of the immune system is remodelled when disease becomes critical.

Perhaps the most clinically consequential finding is the set of genes capable of discriminating between disease states. The study identified transcripts that distinguish asymptomatic or mild SARS-CoV-2 infection from severe disease, that separate healthy children from those with severe COVID-19, and that differentiate RSV-associated illness and pulmonary tuberculosis from one another and from SARS-CoV-2. IFI27, an interferon-stimulated gene frequently implicated in antiviral responses, appears among the leading markers for both severe SARS-CoV-2 and RSV, while myeloid genes such as MMP8 and DEFA4 anchor the tubercular signature. The authors highlight these discriminators as potential future therapeutic targets, and they could also inform the development of diagnostic tests that distinguish bacterial from viral lower respiratory disease at the point of care, a longstanding goal in paediatric medicine where antibiotic stewardship is critical.

The work carries particular significance for low- and middle-income countries, where the study was conducted and where childhood pneumonia remains a leading cause of death. Most transcriptomic studies of COVID-19 have been performed in high-income settings with predominantly adult cohorts, leaving a gap in knowledge about immune responses in children from populations that bear a disproportionate burden of respiratory disease. By embedding this analysis within well-characterised South African birth and pneumonia cohorts, the researchers have generated reference data that reflect the epidemiological realities of the communities most affected. The study was approved by the research ethics committee of the University of Cape Town and the Western Cape Provincial Research Committee, with written informed consent obtained from mothers at enrolment and renewed annually, and secondary analysis approved by the University of Southampton.

As with any transcriptomic study, the findings describe associations between gene expression and disease state rather than proving causation, and whole blood sampling captures a systemic snapshot that may not fully mirror events within the lung itself. Nevertheless, the convergence of evidence, from differentially expressed genes through pathway enrichment, co-expression networks and cellular deconvolution, paints a coherent picture in which severe paediatric COVID-19 resembles the adult syndrome in its immunological architecture, while mild infection in children is marked by a far more restrained response. The gene signatures identified here, including OLFM4, IFI27, IGF2BP3 and their companions across disease groups, now provide a molecular framework for future studies of why some children deteriorate while most do not, and for the design of interventions aimed at tipping that balance.

Subject of Research: Immune gene expression differences in children with SARS-CoV-2 infection compared with other lower respiratory tract infections

Article Title: Immune transcriptomic differences in paediatric patients with SARS-CoV-2 compared to other lower respiratory tract infections

Article References: Kitaba, N. T., Workman, L., Cohen, C., Baralle, D., Kong, E., Botha, M., Johnson, M., Goldblatt, D., Nicol, M. P., Holloway, J. W., & Zar, H. J. (2026). Immune transcriptomic differences in paediatric patients with SARS-CoV-2 compared to other lower respiratory tract infections. BMC Infectious Diseases. https://doi.org/10.1186/s12879-026-14343-x

Image Credits: AI Generated

DOI: 10.1186/s12879-026-14343-x

Keywords: SARS-CoV-2, COVID-19, children, transcriptomics, gene expression, RSV, pulmonary tuberculosis, lower respiratory tract infection, neutrophil degranulation, interferon signalling, WGCNA, South Africa

Viral mimicry was formally described in 2015, when two landmark studies showed that inhibiting DNA methylation in cancer cells could trigger an interferon response without any actual virus being present. The trigger turned out to be endogenous double-stranded RNA derived from endogenous retroviruses and other repeats that had been derepressed by epigenetic drugs. Since then, a large body of work has mapped how this process works at the molecular level. Many transposable elements, including long interspersed nuclear elements such as LINE1 and short interspersed elements such as Alu, retain vestiges of their viral ancestry, including promoter sequences and the capacity to generate RNA species that form double-stranded structures. Pairs of oppositely oriented Alu elements, known as IR-Alus, can fold into intramolecular double-stranded RNA hairpins that are recognized by innate immune sensors such as MDA5, while PKR and ZBP1 provide additional surveillance routes for endogenous double-stranded RNA and Z-form nucleic acids.

The review emphasizes that viral mimicry is not an accidental by-product confined to drug treatment. Cancer-associated alterations in DNA methylation, histone modifications, splicing and RNA processing routinely generate immunogenic nucleic acids in precancerous cells. Global DNA hypomethylation, a common feature of tumour genomes, relaxes repression at repetitive loci; loss of histone marks such as H3K9me3, mediated by enzymes like SETDB1, or disruption of Polycomb repressive complexes derepresses endogenous retroviruses. Splicing defects, which are pervasive across cancer transcriptomes, can create retained introns and aberrant junctions that form double-stranded RNA or Z-RNA structures sensed by MDA5, PKR and ZBP1. Even mitochondrial double-stranded RNA and cytoplasmic RNA–DNA hybrids derived from R-loops can contribute to the endogenous pool of alarm signals. In this sense, the review argues, the pro-tumorigenic regulatory chaos of transformation is inseparable from the collateral production of viral-like nucleic acids.

Viewed through this lens, viral mimicry emerges as a tumour-suppressive mechanism that shapes tumour evolution from its earliest stages. Cells that activate these antiviral programmes can undergo apoptosis, necroptosis, pyroptosis or translational shutdown driven by PKR, or they can attract immune cells through type I interferon signalling that enhances antigen presentation and cytotoxic lymphocyte activity. Recent work describing viral mimicry as a bottleneck in early cancer evolution, including evidence that the pathway acts as a tumour suppressor in inflammatory contexts such as colitis, supports the idea that most cells attempting transformation are eliminated precisely because they cannot simultaneously disrupt their epigenome and silence the repeats that become exposed. Only clones that acquire effective escape mechanisms survive this selective filter, which is why the review frames viral mimicry escape as a prerequisite rather than an option for malignant cells.

The mechanisms cancer cells use to escape are diverse and, the authors argue, reveal a fundamental dependency. On the transcriptional side, tumours often impose compensatory epigenetic repression on repetitive elements, re-engaging DNA methyltransferases, SETDB1, the RB–EZH2 complex or KDM5B to re-silence retroelements. At the RNA level, the editing enzyme ADAR1 converts adenosine to inosine within double-stranded RNA, destabilizing the structures that immune sensors require and acting as a master regulator of viral mimicry escape; high ADAR1 activity is a hallmark of many tumours and is exploited in leukaemia relapse and other contexts. RNA modifications add another layer: N6-methyladenosine deposited by METTL3 and related machinery can reshape double-stranded RNA to prevent sensor recognition and control the fate of endogenous retroviruses. RNA decay enzymes provide a further escape route, with the exonuclease XRN1 degrading retroelement transcripts, while proteins such as DHX9 and the LINE1 ORF1 protein — which acts like a viral innate immune evasion factor — can chaperone or sequester problematic nucleic acids.

Beyond eliminating the trigger molecules themselves, tumours can dampen the downstream signalling that would translate them into an immune response. Sensor pathways can be epigenetically silenced, as has been described for STING and RIG-I–MAVS components in various cancers; interferon signalling itself can be attenuated through regulators such as USP18 and STAT2, or through negative feedback that blunts the antiviral state. Oncogenic drivers also contribute: mutant KRAS in colorectal cancer impairs DDX60-mediated double-stranded RNA accumulation and viral mimicry, converting immunologically hot tumours into cold ones, while p53 loss has been shown to create chronic viral mimicry pressure that selected clones must overcome. Chemotherapy-resistant breast cancers can switch epigenetic states to evade viral mimicry, illustrating that escape is a dynamic, evolving process throughout tumour progression rather than a one-time event.

The review also connects escape mechanisms to biomarkers and therapeutic vulnerabilities. LINE1 ORF1 protein circulating in the blood has been developed as an ultrasensitive multicancer biomarker, and genome-wide repeat landscapes measurable in cell-free DNA reflect the extent of repeat deregulation in individual tumours. Ratios of stemness to interferon signalling have been proposed as biomarkers of progression in myeloproliferative neoplasms. More importantly, every escape mechanism creates a dependency: tumours that rely on ADAR1, XRN1, DHX9, SETDB1 or m6A machinery to survive their own endogenous viral alarm are theoretically vulnerable to drugs that disable those factors. Pharmacological reactivation of viral mimicry — through DNA methyltransferase inhibitors, EZH2 inhibitors, LSD1 inhibitors, spliceosome-targeted therapies, PRMT inhibition or METTL3 blockade — has been shown in preclinical models to restore immunogenicity, and several such approaches are now entering clinical testing.

Combining viral mimicry induction with immunotherapy is a central translational theme. Because viral mimicry activation enhances antitumour immunity and sensitizes cells to immune checkpoint blockade, epigenetic priming with DNMT inhibitors followed by anti-PD1 therapy has shown promise, including in relapsed or refractory NK/T-cell lymphoma, where one of the first trials demonstrating that triggering viral mimicry could augment checkpoint immunotherapy has now been reported. Similar synergy has been observed with EZH2 inhibition in prostate cancer and glioblastoma models, with ZBP1-driven immunogenicity in HER2-directed combinations, and with strategies that restore cGAS–STING and RIG-I–MAVS signalling. Conversely, the review notes that sustained type I interferon signalling can also mediate resistance to some therapies, underscoring that timing, context and combination design matter when manipulating these pathways in patients.

By gathering this evidence into a single conceptual model, the authors propose a reframing of malignant transformation itself: cancer is not simply uncontrolled growth, but uncontrolled growth that has necessarily survived an internal antiviral insurgency of its own making. This unifying model explains why escape mechanisms are so consistently observed across tumour types, why they map onto established dependencies, and why deliberately reactivating viral mimicry represents a rational strategy to expose tumours to their own genome once again. If the framework holds up under experimental and clinical scrutiny, the ancient viral fossils scattered through human DNA may prove to be one of oncology’s most powerful untapped weapons — an alarm that every successful cancer has had to silence, and that medicine may now learn to ring.

Subject of Research: Viral mimicry escape mechanisms in malignant transformation and cancer immunotherapy

Article Title: Viral mimicry escape as a necessary feature of malignant transformation

Article References: Viral mimicry escape as a necessary feature of malignant transformation. (n.d.). https://doi.org/10.1038/s41568-026-00977-1

Image Credits: AI Generated

DOI: 10.1038/s41568-026-00977-1

Keywords: viral mimicry, transposable elements, malignant transformation, epigenetics, interferon signalling, endogenous retroviruses, ADAR1, immune checkpoint blockade, DNA methylation, cancer immunotherapy, innate immunity, double-stranded RNA