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