The patient’s story began four months earlier with persistent watery diarrhea and recurrent abdominal discomfort that failed to respond to standard therapy for gastritis and duodenitis. Initial blood counts at a local hospital revealed a subtle but telling anomaly: an absolute monocyte count of 1.54 × 10⁹ per liter, above the normal threshold, together with a low platelet count of 66 × 10⁹ per liter. By the time he reached the referral center, his hemoglobin had fallen from 147 to 100 grams per liter, his platelets had dropped further to 62 × 10⁹ per liter, and his monocyte count had climbed to 1.93 × 10⁹ per liter. His spleen was enlarged, and his alkaline phosphatase — an enzyme normally kept below 125 units per liter — had skyrocketed to 1,145.3 units per liter, a biochemical red flag for infiltrative disease in bone and liver.

Imaging deepened the mystery. Contrast-enhanced computed tomography showed a spleen roughly 13 centimeters long studded with mildly enlarged retroperitoneal lymph nodes. Positron emission tomography using fluorodeoxyglucose revealed a gastric wall burning with metabolic activity at a maximum standardized uptake value of 19.1 — a figure more typical of aggressive lymphoma than of chronic indigestion — along with diffusely increased uptake in the spleen and mild hypermetabolism in mediastinal and abdominal nodes. Yet endoscopic biopsies of the stomach and duodenum showed only chronic active gastritis and ulcers, with no infiltrative lesions. The mismatch between spectacular metabolic signals and bland biopsy results pointed the team toward the bone marrow.

What they found there was extraordinary. The marrow biopsy showed dense, multifocal infiltrates of atypical mast cells consuming roughly half of the marrow cellularity, accompanied by grade MF-2 to MF-3 reticulin fibrosis. The aspirate smears told a more nuanced story: atypical mast cells made up 18.5 percent of nucleated cells, just under the 20 percent threshold that the current WHO classification requires for a diagnosis of mast cell leukemia. Because an adequate aspirate was available, the biopsy burden alone could not override that criterion, so the team classified the disease as advanced systemic mastocytosis rather than the leukemic variant. The mast cells displayed the classic aberrant phenotype — bright CD117 with inappropriate CD25 expression — and were positive for tryptase on immunohistochemistry.

Next-generation sequencing locked in the molecular diagnosis. The panel detected the KIT D816V mutation, the pathogenic engine of more than 90 percent of adult systemic mastocytosis cases, at a variant allele frequency of 12.1 percent. But the sequencing revealed far more than a mast-cell clone. A frameshift mutation in TET2 at 64.9 percent variant allele frequency marked a founding epigenetic clone, compounded by a deletion of TET2 exons 3 through 11 — evidence of biallelic inactivation. A SRSF2 p.Pro95Arg splice-factor mutation at 44.6 percent and two independent RUNX1 mutations completed a mutational triad that is a hallmark of CMML. A CEBPA nonsense mutation rounded out the profile. Together with sustained absolute monocytosis lasting more than three months and a flow-cytometric finding that 98 percent of the patient’s monocytes were of the classical CD14-positive, CD16-negative subset, the molecular data satisfied WHO and International Consensus Classification criteria for CMML-1 of the proliferative subtype.

Then came the third clone. Serum free light-chain testing showed lambda light chains elevated to 2,274.69 milligrams per liter against a kappa of just 28.98, crushing the kappa/lambda ratio to 0.0127 — roughly fiftyfold below the lower limit of normal. Immunofixation of serum and urine confirmed a monoclonal lambda component. Flow cytometry identified a lambda-restricted plasma-cell population, and fluorescence in situ hybridization on enriched CD138-positive cells revealed the t(11;14)(q13;q32) translocation fusing the immunoglobulin heavy-chain locus to CCND1, the cyclin D1 gene. Bone marrow biopsy showed at least 20 percent CD138-positive plasma-cell infiltration. Yet the team stopped short of calling it multiple myeloma: no myeloma-defining event was documented, since plasma cells remained below 60 percent, the involved/uninvolved light-chain ratio was about 78.5 rather than above 100, and PET-CT showed no focal bone lesions. They classified it conservatively as a t(11;14)-positive plasma-cell neoplasm under surveillance.

The biology behind this triple concurrency is what makes the case scientifically rich. Systemic mastocytosis with an associated hematologic neoplasm is itself not rare — roughly 30 to 40 percent of systemic mastocytosis patients harbor a second blood cancer, and CMML accounts for about a quarter to a third of those associations. The prevailing model holds that KIT D816V, TET2, and RUNX1 mutations arise in an early hematopoietic progenitor with multilineage potential, which then branches into mast-cell-dominant and monocyte-dominant subclones. This patient’s mutation profile — KIT D816V alongside TET2, SRSF2, and RUNX1 — fits that shared-ancestor model precisely. The plasma-cell disorder, however, is almost certainly an independent B-lineage event. Only isolated case reports have ever linked systemic mastocytosis with plasma-cell dyscrasias, and none have documented all three diseases simultaneously. Mechanistically, mast cells can secrete interleukin-6 and stem cell factor, cytokines known to support myeloma cell survival, and can engage CD40-CD154 signaling that promotes lymphoplasmacytic proliferation — possible, if speculative, links between the clones.

Treatment was tailored to the two clinically active components. The team initiated avapritinib, a potent and selective inhibitor of KIT D816V that overcomes the imatinib resistance conferred by that mutation, combined with azacitidine, a hypomethylating agent directed at the CMML clone and its TET2/SRSF2/RUNX1 signature. Venetoclax, which has shown activity in t(11;14)-positive myeloma, was deliberately withheld because the plasma-cell neoplasm had no documented myeloma-defining event and was not the immediate threat. After three cycles, the results were encouraging: the frequency of watery diarrhea decreased substantially, hemoglobin and platelet counts improved, the absolute monocyte count declined, and the alkaline phosphatase began trending downward. The authors note that overlapping myelosuppression from both drugs — azacitidine’s anemia, neutropenia, and thrombocytopenia, and avapritinib’s thrombocytopenia, bleeding risk, and cognitive effects — demanded careful monitoring. Serial light-chain measurements were unavailable during follow-up, so the plasma-cell clone’s response could not be formally assessed.

Beyond its rarity, the case is a pointed argument for diagnostic integration. No single abnormality in this patient could explain the full picture: the mast-cell disease accounted for the diarrhea and the alkaline phosphatase but not the monocytosis; the CMML explained the monocytes and cytopenias but not the lambda light chains; the plasma-cell clone explained neither the mast-cell burden nor the gastric hypermetabolism. Only by weaving together morphology, multiparameter flow cytometry, immunohistochemistry, FISH cytogenetics, and targeted sequencing could the team assemble three coherent diagnoses from one confusing clinical presentation. For clinicians, the lesson is that when a patient’s findings exceed what one hematologic disease can produce, the marrow — examined with every modern tool — may be hiding more than one answer.

Subject of Research: Coexistence of systemic mastocytosis, chronic myelomonocytic leukemia, and a t(11;14)-positive plasma-cell neoplasm in one patient

Article Title: Case Report: Coexistence of advanced systemic mastocytosis, chronic myelomonocytic Leukemia, and t(11;14)-positive plasma-cell neoplasm: a rare triple-clonal hematologic case

Article References: Yin, J., Luo, J., Huang, L., Wang, L., Zhong, M., Li, M., & Huang, S. (2026). Case Report: Coexistence of advanced systemic mastocytosis, chronic myelomonocytic Leukemia, and t(11;14)-positive plasma-cell neoplasm: a rare triple-clonal hematologic case. Frontiers in Oncology, 16, Article 1982665. https://doi.org/10.3389/fonc.2026.1982665

Image Credits: AI Generated

DOI: 10.3389/fonc.2026.1982665

Keywords: systemic mastocytosis, chronic myelomonocytic leukemia, plasma-cell neoplasm, KIT D816V, TET2, SRSF2, RUNX1, t(11;14), avapritinib, azacitidine, bone marrow diagnostics, SM-AHN

The new research, published in Experimental Biology and Medicine, used a statistical technique called Mendelian randomization to ask whether CHIP is merely a bystander in cancer or an active contributor to tumor development. Drawing on genome-wide association data from more than 612,000 cancer cases across 18 tumor types, the team found that people genetically predisposed to CHIP showed increased risks of thyroid cancer, lung cancer, kidney cancer, brain cancer, basal cell carcinoma, and malignant melanoma. The associations held up after stringent statistical corrections and multiple sensitivity checks, offering some of the strongest evidence yet that CHIP is not just a correlate of cancer but potentially a causal player.

CHIP is defined by the expansion of blood stem cells carrying somatic mutations, most often in genes such as DNMT3A, TET2, and ASXL1, at a variant allele frequency above 2 percent, in the absence of any diagnosed blood disorder. It becomes steadily more common with age, appearing in a substantial fraction of people over 70. These mutated clones produce immune cells with altered surface markers and inflammatory behavior, and researchers have proposed that this chronic, low-grade inflammatory state could create fertile ground for malignant transformation in nearby or distant tissues.

Establishing causality between CHIP and cancer has been difficult. Observational studies are confounded by aging itself, by chemotherapy and radiation treatments that can induce CHIP-like mutations, and by the possibility that cancer or its therapy drives the clonal expansions rather than the reverse. Mendelian randomization sidesteps these problems by using naturally occurring genetic variants as proxies for the exposure of interest. Because alleles are randomly assigned at conception, they are largely immune to the confounding and reverse causation that plague conventional epidemiology, and they capture the lifelong effect of a trait rather than a snapshot in time.

The researchers built genetic instruments for CHIP from a large-scale genome-wide association study in European cohorts, selecting independent variants at genome-wide significance and validating them with F-statistics well above the threshold for weak-instrument bias. As a positive control, they confirmed that their CHIP instruments predicted lymphoid leukemia, the association most firmly established in prior clinical work. They then tested these instruments against summary statistics for 18 cancers drawn from the FinnGen consortium, the Million Veteran Program, the PLCO study, and large international consortia, using inverse-variance weighted models as the primary analysis and applying Bonferroni corrections across all tested pairs.

The results were striking in their selectivity. Of the 18 cancers examined, six showed robust associations with genetically predicted CHIP. Brain cancer showed the largest effect, with a pooled odds ratio of 1.78 for overall CHIP, meaning that a genetically predicted one-standard-deviation increase in CHIP liability was associated with roughly a 78 percent higher risk. Thyroid cancer, kidney cancer, lung cancer, basal cell carcinoma, and malignant melanoma all showed elevated odds as well, with DNMT3A-mutant CHIP, the most common subtype, consistently implicated. Notably, the study found no causal signal for breast, prostate, ovarian, colorectal, or several other common cancers, suggesting that CHIP’s influence is highly tissue-dependent rather than a blanket cancer risk.

The histological breakdown added further nuance. Within lung cancer, the association was concentrated in lung adenocarcinoma, with an odds ratio of 1.48, while squamous cell carcinoma and small cell lung carcinoma showed no significant link. In kidney cancer, the effect was driven primarily by clear cell renal cell carcinoma, and in thyroid cancer by papillary adenocarcinoma. This subtype specificity hints that the tumor microenvironment, immune composition, and tissue-specific inflammatory cues determine whether CHIP-mutant immune cells can promote or sustain malignancy in a given organ.

Mechanistically, the findings align with a growing body of work showing that CHIP-mutant myeloid cells can infiltrate solid tumors and reprogram the immune landscape. Recent studies have documented that primary tumors from patients with CHIP contain a higher proportion of myeloid cells, and animal models have demonstrated that TET2-mutant macrophages can either accelerate or, in some contexts, enhance antitumor immunity depending on the setting. The pathway enrichment analysis in the new study pointed to genes involved in DNA damage response, hematopoietic stem cell regulation, and telomere biology, suggesting that CHIP sits at the intersection of clonal selection, genomic instability, and inflammatory remodeling of the tumor niche.

The authors caution that their analysis has limits. The genetic instruments proxy CHIP liability rather than measuring the mutated cells directly, statistical power was limited for some rarer cancers and subtypes, and the study included only European-ancestry cohorts, which may limit generalizability. They also could not fully rule out horizontal pleiotropy, though sensitivity analyses excluding variants near the TERT and TP53 loci, leave-one-out analyses, and MR-Egger intercept tests all supported the robustness of the core findings. Reverse Mendelian randomization showed no evidence that cancer susceptibility drives CHIP, reinforcing the direction of the causal arrow.

If the findings are confirmed in prospective cohorts and across diverse populations, they could reshape how clinicians think about cancer screening in aging adults. CHIP is already detectable through routine blood DNA sequencing, and the researchers argue that timely screening for CHIP could identify people at elevated risk for specific cancers before disease manifests. As the population ages and CHIP becomes an increasingly recognized feature of human biology, the line between normal aging of the blood and a predisposition to malignancy may prove thinner than anyone expected.

Subject of Research: The causal relationship between clonal hematopoiesis of indeterminate potential and cancer risk

Article Title: Causal association between clonal hematopoiesis indeterminate potential and cancer: a Mendelian randomization study

Article References: Jin, J., Pu, Q., Wu, C., Lei, Y., Hu, Y., Yang, X., Huang, J., Wu, F., Xiao, L., & Yu, L. (2026). Causal association between clonal hematopoiesis indeterminate potential and cancer: a Mendelian randomization study. Experimental Biology and Medicine, 251, Article 10923. https://doi.org/10.3389/ebm.2026.10923

Image Credits: AI Generated

DOI: 10.3389/ebm.2026.10923

Keywords: clonal hematopoiesis, CHIP, Mendelian randomization, cancer risk, DNMT3A, TET2, thyroid cancer, lung cancer, kidney cancer, brain cancer, melanoma, tumor microenvironment

DNA methylation is chemically simple: a methyl group is attached to cytosine bases, most often at cytosine-guanine dinucleotides known as CpG sites, catalysed by enzymes called DNA methyltransferases. Yet the consequences are profound. Methylated promoters can silence genes, methylation patterns define chromatin states, and the overall methylation landscape helps keep the genome structurally stable. As the editors of the Research Topic, Pietro Salvatore Carollo of the University of Enna Kore, Andrea Fuso of Sapienza University of Rome and Viviana Barra of the University of Palermo, frame it, DNA methylation acts as the critical software that executes precise cellular programs within the genome’s hardware. When that software is corrupted, the result can be inappropriate silencing or activation of genes, altered chromatin, genomic instability or the disruption of developmental programs, which is why methylation patterns are increasingly treated as predictors of health rather than mere byproducts of it.

Crucially, methylation is not a static feature of the genome. It responds to developmental environment and cellular cues, adapting dynamically and profoundly affecting cellular function and identity. That dynamism cuts both ways: depending on the biological context, a change in methylation may be the initiator of a pathological cascade or simply the consequence of a cell that has already gone awry. Disentangling cause from effect is one of the central challenges of modern epigenetics, and it is precisely the question that unites the six contributions gathered in this collection, which the editors organise into three strands: the enzymology of active demethylation, the methylation-based measurement of biological age, and methylation signatures in inflammatory and chronic disease.

The first strand centres on TET2, a member of the Ten-Eleven Translocation family of enzymes that mediate active DNA demethylation. While methyltransferases write the mark, TET enzymes erase it, and the process is far more intricate than simple reversal. TET2 catalyses the first step of the cascade, oxidising 5-methylcytosine, the canonical methylated base, into 5-hydroxymethylcytosine, an intermediate that carries its own regulatory meaning and can be further oxidised or passively diluted through cell division. In a review by Tang and colleagues, the authors survey how wild-type TET2 maintains cellular physiology and genetic stability, while somatic mutations in the gene are implicated in a striking range of pathologies, from inflammatory disorders to cancers. Because demethylation involves complex multi-step enzymatic cascades whose fine-tuning is still being worked out, understanding TET2’s behaviour in pathological contexts is viewed as a promising route to new therapeutic strategies, exploiting the fact that methylation, unlike the underlying DNA sequence, is chemically reversible.

The second strand turns to time. In 2013, Steve Horvath introduced the concept of the epigenetic clock, showing that variations in DNA methylation patterns across human tissues and cell types correlate with ageing phenotypes. Since then, a family of epigenetic clocks has been developed, and they can now be applied not only to individual tissues but to populations and to specific pathological contexts. Chen and colleagues review the mechanistic basis of these methylation-based age estimates and their expanding implications for ageing research, health monitoring and disease prediction. The idea that a blood sample can yield a molecular readout of biological age, one that may diverge from chronological age and predict disease risk, has moved epigenetics from the laboratory bench into preventive medicine, and the review charts both the technical progress and the open questions in the field.

The third strand delivers some of the collection’s most concrete clinical findings. In rheumatoid arthritis, an autoimmune disease characterised by chronic joint inflammation and erosion, Delgado-Cruzata and colleagues examined cell-free DNA, fragments of genetic material circulating in plasma, from 27 patients. Using pyrosequencing, a quantitative method that reads methylation levels at individual CpG sites, they found that patients displayed lower methylation of the DUSP22 gene promoter at one specific site compared with healthy controls. More strikingly, decreased methylation levels in circulating DNA were associated with increased joint space narrowing, a radiographic marker of disease progression. The result points toward cell-free DNA methylation as a new, non-invasive biomarker for rheumatoid arthritis, potentially allowing clinicians to track erosive disease from a simple blood draw.

Hypertension tells a similar story of methylation as a disease mirror. Zhu and colleagues used Illumina Infinium Methylation EPIC BeadChips, arrays capable of interrogating hundreds of thousands of CpG sites across the genome, to profile methylation in peripheral leukocytes from 179 patients with high blood pressure. Their epigenome-wide analysis uncovered associations between altered methylation patterns and inflammation biomarkers, reinforcing the emerging view that hypertension is not solely a vascular or haemodynamic disorder but one with a measurable inflammatory and epigenetic dimension. Patterns like these could eventually help stratify patients who respond differently to treatment, or flag individuals at risk before blood pressure becomes chronically elevated.

Inflammation also takes centre stage in neonatal medicine. Sankar and colleagues studied newborns with late-onset neonatal sepsis, a devastating bacterial infection that strikes after the first days of life. Infants with the condition displayed a distinctive methylation signature: pro-inflammatory genes were hypomethylated, a state generally permissive of gene expression, while anti-inflammatory genes were hypermethylated, relative to healthy newborns. The expression of key cytokines, including TNF-α, IFN-γ, IL-10 and TGF-β, was accordingly shaped by methylation status. Because neonatal sepsis is notoriously difficult to diagnose quickly, a methylation-based signature could improve both diagnostics and therapy, identifying which infants mount a runaway inflammatory response and guiding interventions before organ damage occurs.

The final study demonstrates how methylation profiles can capture the interplay of disease, sex and geography. Miranda-Morales and colleagues performed bisulfite pyrosequencing on leukocyte DNA from Parkinson’s disease patients and age- and sex-matched healthy individuals in the Mexican Mestizo population, targeting CpG sites within two genes central to the disease: MAPT, which encodes the tau protein, and SNCA, which encodes alpha-synuclein, the main component of the protein aggregates that define the disorder. Patients showed reduced methylation in the MAPT promoter region and in intron one of SNCA. Intriguingly, the methylation differences were sex-specific: men displayed significant differences in MAPT methylation, while women showed significant differences at SNCA. Patterns also varied with regional location within the population, establishing that sex- and geography-specific methylation signatures exist in Parkinson’s disease, with implications for how epigenetic risk is assessed across diverse populations.

Taken together, the six studies converge on a common theme that is reshaping biomedical research: DNA methylation is a dynamic, responsive layer of genome regulation whose disturbances both reflect and drive human disease. By combining multi-omic and clinical data, the field is evolving from the identification of individual methylation loci toward an integrated view of disease biology, one that clarifies the mechanisms underlying disease heterogeneity and uncovers molecular signatures with value for diagnostics, prognosis and therapy. And because methylation is reversible in a way that genetic mutations are not, aberrant patterns represent an inviting therapeutic target. From the demethylase activity of TET2 to the ticking of epigenetic clocks and the methylation signatures circulating in a drop of blood, the software of the genome is proving to be not just a record of disease, but a place where disease might be rewritten.

Subject of Research: The role of DNA methylation in human diseases, including TET2-mediated demethylation, epigenetic clocks, and methylation biomarkers in inflammatory and neurodegenerative conditions.

Article Title: Editorial: Discussing the implication of DNA methylation in human diseases

Article References: Carollo, P. S., Fuso, A., & Barra, V. (2026). Editorial: Discussing the implication of DNA methylation in human diseases. Frontiers in Molecular Biosciences, 13, Article 2015661. https://doi.org/10.3389/fmolb.2026.2015661

Image Credits: AI Generated

DOI: 10.3389/fmolb.2026.2015661

Keywords: DNA methylation, epigenetics, TET2, epigenetic clock, cell-free DNA, rheumatoid arthritis, hypertension, neonatal sepsis, Parkinson's disease, biomarkers, ageing, gene expression

The machine in question is the CUL4-RING E3 ligase, or CRL4, a multi-component enzyme complex that normally serves as the cell’s quality-control apparatus. E3 ligases are the recognition modules of the ubiquitin-proteasome system: they bind specific target proteins and catalyze the attachment of ubiquitin chains, molecular tags that mark a protein for destruction by the proteasome. CRL4 accomplishes this through a scaffold protein called CUL4, a catalytic RING protein, and an adaptor known as DDB1, which in turn docks a substrate receptor that determines what gets destroyed. In uninfected cells, this system helps regulate DNA replication, DNA repair and other essential processes.

HIV-1 subverts this machinery with elegant economy. Rather than building its own degradation apparatus, the virus deploys Vpr, which binds to a cellular substrate receptor called VprBP, also known as DCAF1. Once Vpr docks onto VprBP, the viral protein acts as a mutable adaptor that can recruit a shifting cast of host proteins into the CRL4(VprBP) complex, delivering them to the catalytic core for ubiquitination and proteasomal degradation. Among the confirmed victims are restriction factors and regulators such as UNG2, a uracil-DNA glycosylase involved in DNA repair, and TET2, an enzyme that chemically modifies DNA. By degrading these factors, Vpr helps the virus counteract innate and intrinsic immune defenses and manipulate the cellular environment to favor replication.

What has puzzled structural biologists for years is how a single receptor-adaptor pair can accommodate substrates as chemically and structurally divergent as UNG2 and TET2. The new study addresses this question by determining cryo-electron microscopy structures of the DDB1-VprBP substrate recognition unit on its own and in complex with different Vpr-substrate assemblies. These structures capture the machinery in multiple conformational states, allowing the researchers to trace how the complex physically reorganizes itself to grip targets of different stoichiometries and dimensions.

The first key finding concerns the architecture of the receptor itself. VprBP is a large protein containing several domains, including a LisH domain and two Armadillo-like repeat domains, often abbreviated ARM-like domains, which form elongated, curved surfaces well suited to protein-protein interactions. The structures show that the LisH domain of VprBP is responsible for mediating dimerization of the DDB1-VprBP unit. This dimerization is not a trivial detail: it doubles the number of binding surfaces available and creates a symmetric platform on which two copies of a substrate can be engaged simultaneously. The LisH domain, a motif named for the Lis1 homology region where it was first characterized, has previously been implicated in oligomerization in other proteins, and this study confirms its structural role as the dimerization engine of the VprBP receptor unit.

The second and perhaps most striking discovery is the conformational plasticity of the ARM-like domains. In the structures, these domains are seen adopting two distinct orientations, which the authors describe as an up conformation and a down conformation. When the complex is bound to UNG2, a relatively small substrate, the two ARM-like domains in the up position wrap around and directly contact two symmetrically arranged UNG2 molecules, one on each side of the dimerized receptor unit. This arrangement effectively clamps the small substrate between the curved ARM-like surfaces, explaining how the complex achieves high-affinity recognition of a compact target.

When the researchers examined the complex bound to a larger fragment of TET2, however, the picture changed dramatically. The ARM-like domains swung into the down conformation, repositioning themselves to accommodate the bulkier substrate. This switch illustrates a structural principle that has emerged from studies of other multidomain receptors: conformational dynamics, rather than rigid lock-and-key binding, can allow a single scaffold to recognize chemically unrelated targets. In the case of VprBP, the up-to-down transition of the ARM-like domains appears to be the mechanical solution that lets the CRL4(VprBP) complex handle substrates ranging from compact enzymes to larger multi-domain proteins.

The implications for HIV biology are significant. Vpr’s ability to degrade diverse host factors is central to several aspects of viral pathogenesis, including the manipulation of the cell cycle, the modulation of DNA damage responses and the evasion of restriction factors. By showing exactly how Vpr-bound substrates are presented to the receptor, the new structures provide a mechanistic framework for understanding how the virus co-opts the host ubiquitin system. They also suggest that the flexibility of the ARM-like domains may be a general feature that permits Vpr, and possibly related viral proteins such as Vpx in HIV-2 and SIV, to recruit an evolving repertoire of substrates as the virus adapts to different host environments.

Beyond virology, the study has direct relevance to the booming field of targeted protein degradation. Pharmaceutical researchers have increasingly sought to repurpose E3 ligases as engines for degrading disease-causing proteins, designing bifunctional molecules that tether a target protein to an E3 ligase so that the cell destroys it. The CRL4(VprBP) system is particularly attractive for such efforts because Vpr demonstrates that the receptor can be induced to accept many different substrates. The new structures, by revealing the binding surfaces and conformational states that enable this promiscuity, could guide the structure-guided design of degraders that exploit VprBP to eliminate therapeutic targets, from oncogenic proteins to other disease drivers.

The work also underscores how much remains to be learned about the structural logic of viral hijacking. Each new structure of a hijacked E3 ligase reveals a different strategy: some viral proteins mimic natural substrate receptors, others insert themselves as adaptors, and still others remodel the receptor to change its specificity. The Vpr-VprBP system now stands as a textbook example of the adaptor strategy, with the added twist that the receptor itself is conformationally dynamic. As structural biologists continue to capture these machines in action, the boundary between viral manipulation and therapeutic engineering grows thinner, and the same molecular flexibility that HIV-1 exploits to evade immunity may one day be harnessed to treat human disease.

Subject of Research: Structural mechanism of substrate recruitment by the HIV-1 Vpr-hijacked CRL4(VprBP) E3 ubiquitin ligase

Article Title: Structural basis of diverse substrate recruitment by the HIV-1 Vpr-hijacked CRL4(VprBP) E3 ligase

Article References: Wang, D., Ding, W., Xu, J., Li, R., Cairoli, T., Liu, Q., Zhu, Y., & Xiang, Y. (2026). Structural basis of diverse substrate recruitment by the HIV-1 Vpr-hijacked CRL4(VprBP) E3 ligase. PLOS Pathogens, 22(10), e1014610. https://doi.org/10.1371/journal.ppat.1014610

Image Credits: AI Generated

DOI: 10.1371/journal.ppat.1014610

Keywords: HIV-1, Vpr, VprBP, CRL4, E3 ligase, DDB1, UNG2, TET2, cryo-EM, protein degradation, ubiquitin-proteasome system, targeted protein degradation

The research team, led by Adeena Musheer and colleagues working across institutions in Pakistan and the United States, conducted the review according to PRISMA 2020 guidelines, the current international standard for systematic evidence synthesis. They searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and grey literature sources from database inception through December 2025. To be included, studies had to report myeloid neoplasms diagnosed after CAR-T therapy or ASCT and provide extractable data on at least one of three parameters: incidence, latency, or molecular characteristics. Because the included studies varied enormously in design, patient populations, and reporting conventions, the authors synthesized their findings descriptively rather than attempting a meta-analysis, a decision that reflects an honest assessment of the state of the evidence. Nine studies comprising 2,933 patients ultimately met the inclusion criteria, and within those cohorts a total of 195 therapy-related myeloid neoplasm cases were reported.

One of the most striking findings concerns latency, the interval between the initial therapy and the diagnosis of the secondary cancer. The review found that median latency varied widely across studies, but the pattern differed meaningfully between the two treatment modalities. Following CAR-T therapy, reported median latency ranged from just 3 to 78 months, a window that in some cohorts was remarkably short. In contrast, ASCT cohorts reported longer intervals, spanning from 2.4 to as much as 262.8 months, meaning that some secondary leukemias appeared more than two decades after transplantation. This difference in timing is biologically intriguing. CAR-T therapy itself is not a classical DNA-damaging agent in the way that alkylating chemotherapy or total body irradiation are, so the shorter latency observed after CAR-T likely reflects the fact that these patients arrive at the therapy with bone marrows already heavily scarred by prior cytotoxic exposure, with pre-existing mutant clones poised for outgrowth once the selective pressures of treatment remove competing normal hematopoiesis.

That mechanistic picture is supported by the molecular data the review assembled. Half of the included studies assessed clonal haematopoiesis, the age-related phenomenon in which blood cells descended from a single mutated stem cell progressively dominate the marrow. Clonal haematopoiesis is increasingly understood as the soil in which therapy-related myeloid neoplasms grow: pre-leukemic clones carrying mutations in specific genes tolerate chemotherapy better than normal stem cells, expand to fill the void left by treatment, and in some patients acquire additional hits that drive full-blown malignancy. In the studies reviewed, the prevalence of clonal haematopoiesis ranged from 20 percent to over 80 percent, and crucially, higher rates were observed among patients who went on to develop therapy-related myeloid neoplasms. Recurrent mutations in three genes in particular, DNMT3A, TET2, and TP53, were consistently identified across both CAR-T and ASCT cohorts, underscoring that the two treatments share common biological underpinnings for this complication.

The identity of those three genes tells a coherent story. DNMT3A and TET2 are the two most commonly mutated genes in age-related clonal haematopoiesis in the general population, and both encode enzymes involved in DNA methylation regulation, a key epigenetic control mechanism in stem cells. Mutant TET2 and DNMT3A clones are known to be chemotherapy-resistant and to expand preferentially after cytotoxic treatment. TP53, by contrast, is the guardian of the genome, and mutations in it confer both resistance to certain therapies and a propensity toward genomic instability and aggressive leukemic transformation. The consistent finding of TP53 mutations in therapy-related myeloid neoplasms after both CAR-T and ASCT suggests that, in a subset of patients, the seeds of the secondary cancer are present before the transplant or CAR-T infusion even occurs, having been selected and amplified by earlier chemotherapy cycles.

The survival data in the review are sobering and represent perhaps its most clinically consequential message. Once a therapy-related myeloid neoplasm developed, outcomes were poor in both settings, but the prognosis was markedly worse after CAR-T therapy. Patients in CAR-T cohorts had a median overall survival of only 4.5 months following diagnosis of the secondary neoplasm, while ASCT cohorts fared better with a median overall survival of 18.4 months. Several factors could contribute to this disparity. Patients receiving CAR-T in the included studies may have had more heavily pretreated disease, more advanced clonal evolution by the time of the CAR-T infusion, or less reserve to tolerate intensive induction chemotherapy for the secondary leukemia. The authors themselves caution that these observations should be interpreted in the context of heterogeneous study designs and differing degrees of prior treatment exposure, so the comparison between modalities is not a head-to-head trial result but a signal that warrants prospective investigation.

The methodological limitations of the underlying evidence base are significant and the review does not shy away from them. Risk of bias was judged to be moderate to high across the included studies, primarily because of retrospective designs, confounding, and heterogeneity in how outcomes were reported. Retrospective cohort studies are vulnerable to incomplete follow-up, ascertainment bias in detecting secondary cancers, and the impossibility of fully adjusting for the many differences between patients who receive CAR-T versus those who proceed to ASCT. Because pooled incidence estimates could not be calculated, clinicians reading this review will not find a single number they can quote to a patient about their absolute risk. What they will find instead is a consistent qualitative picture: therapy-related myeloid neoplasms are a real and clinically significant complication in both settings, they occur with distinct latency patterns, and they are driven by shared clonal biology.

The implications for clinical practice are already taking shape. As CAR-T therapy expands from relapsed and refractory lymphomas and myelomas into earlier lines of treatment, the population of long-term survivors exposed to this modality is growing rapidly, and the review’s findings argue strongly for structured long-term surveillance of these patients. The authors highlight the need to incorporate molecular risk stratification strategies into the care of heavily pretreated patients. In practical terms, this could mean screening for clonal haematopoiesis before or after CAR-T infusion or transplant, with the presence of high-variant-allele-fraction TP53 or other high-risk mutations flagging patients who merit closer blood count monitoring and earlier referral for evaluation. Such an approach mirrors what is already being explored in solid tumor oncology, where clonal haematopoiesis testing is increasingly used to interpret circulating tumor DNA and to anticipate chemotherapy-associated complications.

For the field at large, this systematic review arrives at a pivotal moment. CAR-T cell therapy is one of the most celebrated advances in cancer medicine of the past decade, producing durable remissions in patients whose disease had exhausted every conventional option, and autologous transplantation remains a cornerstone of treatment for myeloma and lymphoma. The finding that 195 secondary myeloid cancers occurred among roughly 2,900 patients across nine studies does not diminish the value of these therapies, but it does define the frontier of the next challenge: preserving their remarkable benefits while identifying, before treatment, the minority of patients whose marrow clones place them at highest risk of a second malignancy. The review’s central contribution is to consolidate scattered single-center reports into a coherent evidence map, one that shows shorter latency and poorer survival after CAR-T, longer and more variable latency after ASCT, and a common molecular signature rooted in DNMT3A, TET2, and TP53. Converting that map into prospective screening programs, standardized reporting, and ultimately preventive strategies is the task the authors have set for the field, and it is one that will only grow more urgent as these therapies reach ever larger numbers of patients.

Subject of Research: Therapy-related myeloid neoplasms following CAR-T cell therapy and autologous stem cell transplantation

Article Title: Therapy-related myeloid neoplasms after CAR-T therapy and autologous stem cell transplantation: a systematic review of reported incidence, latency, and clonal haematopoiesis

Article References: Musheer, A., Mannan, M. S., Khan, M. W., Bhatti, A., Hafeez, A. S., Junaid, A., & Muhammad, S. (2026). Therapy-related myeloid neoplasms after CAR-T therapy and autologous stem cell transplantation: a systematic review of reported incidence, latency, and clonal haematopoiesis. Annals of Hematology. https://doi.org/10.1007/s00277-026-07305-5

Image Credits: AI Generated

DOI: 10.1007/s00277-026-07305-5

Keywords: therapy-related myeloid neoplasms, CAR-T therapy, autologous stem cell transplantation, clonal haematopoiesis, acute myeloid leukemia, myelodysplastic syndrome, DNMT3A, TET2, TP53, latency, systematic review, hematology

Tet2 is an epigenetic regulator, an enzyme that chemically modifies DNA through the oxidation of 5-methylcytosine, thereby influencing which genes are accessible for transcription. Mutations that impair Tet2 function are extraordinarily frequent in the elderly: they define a large fraction of cases of clonal hematopoiesis of indeterminate potential, or CHIP, the age-related expansion of blood cell clones carrying somatic mutations without overt malignancy. CHIP is a well-established risk factor for myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN) and acute myeloid leukemia (AML), yet the mechanisms by which Tet2 loss translates into such diverse disease outcomes, and why progression accelerates with age, have remained incompletely understood. The new study set out to close that gap with a purpose-built animal model.

Using CRISPR-Cas9 gene editing and the Cre-LoxP recombination system, the team generated Tet2 conditional knockout mice on a C57BL/6JGpt background, in which the gene could be deleted selectively in hematopoietic cells through Mx1-Cre-mediated recombination. This design ensured that the mutation was confined to the blood-forming compartment, mirroring the somatic, tissue-restricted nature of Tet2 mutations in patients. The researchers then systematically characterized hematopoietic phenotypes, pathological features and immune microenvironment dynamics at two ages, five and twelve months, comparing the knockout animals with wild-type littermates. The two time points were chosen to capture, respectively, an early adult stage and a stage corresponding to advanced age in the mouse lifespan.

The results revealed a clear age-dependent trajectory of disease. At five months, the Tet2-deficient mice showed only mild hematological abnormalities and no overt pathology, a picture reminiscent of early clonal hematopoiesis in humans. By twelve months, however, the animals had developed the classic features of myeloid neoplasms: pancytopenia, a depletion of circulating red cells, white cells and platelets; splenomegaly, an enlargement of the spleen reflecting extramedullary blood production; and myelodysplasia, the morphologically abnormal maturation of blood cell precursors in the bone marrow. Crucially, the diseased mice did not converge on a single diagnosis. Instead, they displayed heterogeneous subtypes spanning myelodysplastic syndrome, myeloproliferative neoplasm and acute myeloid leukemia, the very range of outcomes seen in elderly patients carrying Tet2 mutations.

This heterogeneity is one of the study’s most significant contributions. Clinical hematologists have long observed that Tet2-mutated patients progress along different paths, some developing ineffective blood cell production, others overproduction of myeloid cells, and still others frank leukemia, but animal models have struggled to capture this diversity. The finding that a uniform Tet2 deletion in a uniform genetic background produces divergent disease subtypes as mice age suggests that stochastic factors, secondary events or microenvironmental influences, rather than the mutation itself, determine which clinical entity emerges. The model therefore recapitulates not just the existence of Tet2-driven disease but its characteristic unpredictability.

Beneath the hematological phenotypes, the researchers uncovered a profound immune reconfiguration of the bone marrow. Tet2-deficient mice established an immunosuppressive niche characterized by the polarization of macrophages toward an M2-like state, a phenotype associated with tissue repair, immune suppression and tumor promotion. At the same time, the chemokine landscape of the marrow was skewed: levels of CCL22 were elevated while CCL17 was diminished. Both molecules are ligands for the CCR4 receptor, but this altered ligand profile had a selective consequence, preferentially recruiting Foxp3-positive regulatory T cells into the bone marrow. Regulatory T cells are the immune system’s brakes, and their accumulation within the tumor-bearing marrow creates an environment in which malignant clones are shielded from immune surveillance.

The immune perturbation was not confined to the marrow. Serum cytokine profiling revealed broad systemic immune activation spanning Th1-type, Th2-type and Th17-type responses, indicating that Tet2 deficiency provokes a body-wide inflammatory state even as it builds a locally immunosuppressive niche in the bone marrow. This combination, chronic peripheral inflammation alongside local immune evasion, mirrors concepts developed in tumor immunology more broadly and may help explain why patients with clonal hematopoiesis carry elevated risks not only of hematological malignancy but also of inflammatory and cardiovascular disease, although the present study focused on the myeloid neoplasm phenotype.

A further striking observation concerned sex differences. Male mice exhibited significantly accelerated disease progression compared with females, a result that resonates with epidemiological data showing higher rates of clonal hematopoiesis and myeloid neoplasms in elderly men than in elderly women. The biological basis of this disparity remains to be fully elucidated, but its reproduction in a controlled animal model, where environmental and hormonal variables can be standardized, provides a tractable experimental system for dissecting why male biology appears to amplify the consequences of Tet2 loss.

Taken together, the study supports a three-part mechanistic model: Tet2 deficiency drives myeloid neoplasm progression through the synergy of epigenetic dysregulation, age-related damage to hematopoietic stem cells, and imbalance of the immune microenvironment. Age emerges not as a passive backdrop but as an active collaborator, with the passage of time allowing the epigenetically compromised stem cell compartment and the progressively distorted immune niche to reinforce one another until overt malignancy appears. The CCL22-driven recruitment of regulatory T cells and the M2-like polarization of macrophages offer concrete, mechanistically defined targets at the interface between the mutant clone and its surroundings.

The translational implications are considerable. Because the model recapitulates the core clinical features of elderly Tet2-mutated myeloid neoplasms, including their heterogeneity, their age dependence and their immune microenvironment signatures, the authors position it as a preclinical platform for both mechanistic investigation and therapeutic development. Epigenetic therapies aimed at restoring or compensating for lost Tet2 function could be tested alongside immune-targeted approaches designed to reverse macrophage polarization, block CCR4-mediated recruitment of regulatory T cells, or rebalance the systemic cytokine storm. As the population ages and Tet2-mutated clonal hematopoiesis becomes an increasingly common incidental finding, models of this kind will be essential for deciding which carriers need intervention, and which of the emerging epigenetic and immunotherapeutic strategies can prevent a silent clone from becoming a lethal cancer.

Subject of Research: Tet2 deficiency and age-related progression of myeloid neoplasms through epigenetic and immune microenvironment dysregulation

Article Title: Tet2 deficiency drives age-related heterogeneous progression of myeloid neoplasms through epigenetic-immune microenvironment imbalance

Article References: Chen, Y., Yu, L., Yang, R., Chen, P., Zeng, W., Li, Z., Wang, Y., Xu, Y., & Yang, X. (2026). Tet2 deficiency drives age-related heterogeneous progression of myeloid neoplasms through epigenetic-immune microenvironment imbalance. Journal of Translational Medicine, 24(1), Article 1160. https://doi.org/10.1186/s12967-026-08835-2

Image Credits: AI Generated

DOI: 10.1186/s12967-026-08835-2

Keywords: Tet2, clonal hematopoiesis, myeloid neoplasms, myelodysplastic syndrome, acute myeloid leukemia, epigenetics, bone marrow microenvironment, macrophage polarization, regulatory T cells, CCR4, mouse model, aging

Clonal hematopoiesis arises when a hematopoietic stem or progenitor cell acquires a mutation — commonly in genes such as DNMT3A, TET2, ASXL1, TP53, or JAK2 — and its descendants expand to occupy a measurable fraction of the blood cell population. The phenomenon becomes increasingly prevalent with age, and its presence in apparently healthy people without hematologic malignancy is termed clonal hematopoiesis of indeterminate potential, or CHIP. When cytopenias are also present, the designation shifts to clonal cytopenia of undetermined significance. The critical issue for oncology is that these mutations are indistinguishable, at the sequence level, from somatic alterations driving cancer. A TP53 variant detected in a plasma sample from a patient with suspected lung cancer could be a genuine tumor-derived alteration circulating as cell-free DNA, or it could be leaking into the assay from a large clone of mutated white blood cells. The distinction changes everything about how the result is interpreted and acted upon.

The review’s first domain, Domain A, addresses variant-origin assessment, and here the authors are emphatic about the hierarchy of evidence. Matched white blood cell sequencing provides the most direct comparator: if a variant detected in tumor tissue or plasma is also present in the patient’s leukocytes, a hematopoietic source is strongly supported. This paired-specimen approach is technically straightforward but is not yet universally practiced, particularly in plasma-based assays where white blood cell sequencing is often omitted for cost or workflow reasons. When matched sequencing is unavailable, the authors note that complementary lines of evidence can help — concordance between the variant in tumor and plasma, longitudinal dynamics of the variant over time, fragmentomic features of the cell-free DNA molecules carrying it, and appropriately validated computational models that attempt to infer tissue of origin. But they insist on a crucial epistemic rule: when the origin of a variant cannot be resolved, it should remain classified as indeterminate rather than being forced into a tumor or blood category for the sake of a complete report.

The consequences of failing to make this distinction ripple through every layer of modern molecular oncology. Tumor genotyping can be distorted when hematopoietic contamination inflates apparent mutation frequencies or introduces variants that were never present in the cancer cells themselves. Circulating tumor DNA interpretation, the backbone of noninvasive genotyping and treatment selection, is vulnerable to false positives from leukocyte-derived cell-free DNA. Perhaps most consequential is molecular residual disease assessment, the rapidly growing practice of using ultra-sensitive ctDNA assays after surgery or curative-intent therapy to detect microscopic residual cancer. A persistent hematopoietic clone shedding cell-free DNA can mimic residual disease, potentially triggering unnecessary adjuvant treatment, or conversely can mask true tumor signal. The review frames these risks not as theoretical curiosities but as systematic threats that demand workflow-level solutions, including routine paired white blood cell sequencing as a standard component of liquid biopsy pipelines.

Domain B of the framework shifts perspective entirely. Once a variant has been established as hematopoietic in origin, clonal hematopoiesis ceases to be a source of error and becomes a candidate host variable — a feature of the patient rather than the tumor. But the authors warn against treating it as a single binary attribute. They enumerate the structured dimensions that must be captured for any meaningful analysis: the genotype, meaning the specific mutated gene; the exact variant within that gene, since different mutations in the same gene can have different functional consequences; the clone size, typically estimated by variant allele fraction in blood; co-detected alterations within the same clone or in parallel clones; the lineage contribution, meaning which blood cell types the clone has infiltrated; prior treatment exposures such as chemotherapy or radiotherapy that may select for or against particular clones; the timing of sampling relative to diagnosis and therapy; and longitudinal behavior, whether the clone is expanding, contracting, or stable. A TET2-mutant clone at two percent variant allele fraction that has been stable for years is, in this framework, a fundamentally different biological entity from a TP53-mutant clone at fifteen percent that emerged after cytotoxic chemotherapy.

Domain C confronts the seductive hypothesis that clonal hematopoiesis might serve as a prognostic or predictive biomarker in solid-tumor care. The biological plausibility is real: mutated hematopoietic clones, particularly those with TET2 loss, have been shown in mechanistic studies to alter inflammatory signaling and immune function, including through elevated production of inflammatory cytokines and altered macrophage polarization. This has fueled speculation that patients carrying such clones might respond differently to immune checkpoint inhibitors, the checkpoint-blocking antibodies that have transformed treatment of many advanced cancers. The review does not dismiss this hypothesis, but it imposes demanding methodological standards on any study claiming clinical relevance: prespecified features and endpoints declared before analysis, appropriate comparator groups, rigorous control of confounding — a formidable challenge given that clonal hematopoiesis prevalence rises with age, smoking exposure, and therapy history, all of which independently influence cancer outcomes — external validation in independent cohorts, and demonstration of incremental value beyond established tumor and clinical factors already in use.

On the specific question of TET2-mutant clonal hematopoiesis and immunotherapy, the authors draw a line that many in the field will find uncomfortable but necessary. The mechanistic evidence linking TET2 loss to altered antitumor immunity is genuine but model-limited, derived largely from preclinical systems and observational associations. It does not, they argue, constitute a validated basis for selecting or deselecting patients for immune checkpoint inhibitor therapy. In other words, a clinician who sees a TET2 mutation in a patient’s blood panel today should not conclude that the patient will respond better or worse to pembrolizumab or nivolumab. The framework’s insistence on separating biological activity from clinical actionability is perhaps its most important contribution, because the history of biomarker development is littered with plausible mechanisms that failed to survive prospective validation.

Domain D addresses intervention, and here the framework is at its most conservative. For clonal hematopoiesis to justify any therapeutic intervention in the context of solid-tumor care, the authors require a target that is causal in the disease process, measurable with available tools, and safely modifiable — plus evidence of clinical utility and net patient benefit. None of these conditions is currently met. Even in hematology, where CHIP and clonal cytopenia are native concepts, intervention thresholds remain debated, and the idea of treating blood clones to improve cancer outcomes sits far beyond the current evidence base. The authors’ point is not that such interventions are impossible but that the field must resist the temptation to leap from association to action, a leap that has historically produced harm when premature.

The review’s conclusions amount to a roadmap with explicit guardrails. In the near term, laboratories and clinicians should implement origin-aware molecular interpretation: paired white blood cell sequencing where feasible, transparent reporting of variant-origin confidence, and honest preservation of indeterminate classifications rather than forced attributions. In the medium term, the authors call for prospective evaluation of paired-specimen workflows to quantify how much diagnostic accuracy improves when hematopoietic variants are systematically identified, and for genotype-resolved studies of clonal hematopoiesis as a host variable, since pooling all mutations under a single label almost certainly obscures the biology. The framework, published as an open-access article in the Journal of Translational Medicine, arrives at a moment when liquid biopsy volumes are expanding rapidly and molecular residual disease testing is moving toward routine use in early-stage cancers. Whether the field adopts the discipline the authors prescribe may determine whether clonal hematopoiesis becomes a precision oncology asset — or a persistent, avoidable source of misdiagnosis.

Subject of Research: Clonal hematopoiesis as a source of variant misattribution and a candidate host biomarker in solid-tumor precision oncology

Article Title: Clonal hematopoiesis in solid-tumor precision oncology: an intended-use framework for variant-origin assessment, host biomarker evaluation, and intervention boundaries

Article References: Yang, Y., Fu, J., Tang, S., Wen, L., Hu, H., Guo, H., Yang, Y., Liu, C., Yi, G., Yu, L., & Zhou, H. (2026). Clonal hematopoiesis in solid-tumor precision oncology: an intended-use framework for variant-origin assessment, host biomarker evaluation, and intervention boundaries. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-08963-9

Image Credits: AI Generated

DOI: 10.1186/s12967-026-08963-9

Keywords: clonal hematopoiesis, CHIP, precision oncology, liquid biopsy, circulating tumor DNA, molecular residual disease, variant-origin assessment, TET2, immune checkpoint inhibitors, cell-free DNA, biomarker evaluation, white blood cell sequencing

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

Asthma affects hundreds of millions of people worldwide and has long been known to run in families, but the majority of the genetic variants linked to the disease sit in stretches of DNA that do not code for proteins. This so-called missing heritability has frustrated researchers for decades, because it is difficult to know which of these non-coding variants actually change how immune cells behave. The team behind the new study approached the problem from an unusual angle. Rather than asking which variants sit near genes, they asked which variants fall inside or near the chemical docking sites for m6A, the most abundant internal modification found in eukaryotic messenger RNA. These sites are called m6A-SNPs, and emerging evidence suggests they can influence how messenger RNA molecules are read, stabilized, and translated, thereby altering protein output without changing the underlying protein sequence.

To find m6A-regulated genes that matter in asthma, the researchers integrated genome-wide association study data from the UK Biobank, covering both asthma diagnoses and measures of lung function such as forced expiratory volume in one second, forced vital capacity, and peak expiratory flow, with a catalog of m6A-associated variants drawn from the m6AVar database. They then used summary-data-based Mendelian randomization, a statistical framework that borrows genetic variants as instruments to infer whether altered gene expression is a cause or merely a consequence of disease, along with expression quantitative trait loci summary statistics from the Westra and CAGE datasets. This triangulation allowed them to prioritize candidate genes in which genetic variation plausibly changes expression in a way that contributes to asthma risk or impaired lung function.

The analysis converged on TET2, a gene encoding ten-eleven translocation methylcytosine dioxygenase 2, an enzyme best known for its role in DNA demethylation and for its profound influence on innate immune cells. In the study’s genetic models, TET2 was associated not only with asthma susceptibility but also with lung function traits, making it one of the few candidates that satisfied evidence criteria across both disease and physiological endpoints. Importantly, the association passed correction for multiple testing at a false discovery rate threshold, indicating that the signal was unlikely to arise by chance despite the enormous number of variants and genes tested.

Genetic prioritization alone cannot reveal where in the body, or in which cells, the effect takes place, so the team turned to single-cell RNA sequencing of tissue from an ovalbumin-induced mouse model of allergic asthma. This technology profiles the gene expression of thousands of individual cells at once, allowing researchers to map which cell types change their molecular identity as disease develops. The single-cell analysis showed that TET2 was selectively upregulated in monocytes during asthmatic inflammation, and that the monocytes themselves displayed hallmarks of inflammatory activation, including enrichment of pro-inflammatory gene programs and activation of the PI3K signaling pathway, a cellular communication cascade with well-established roles in immune cell survival, migration, and cytokine production. Other immune populations, including T helper cells and tissue-resident memory T cells, showed distinct disease-associated changes, but the monocyte-centered pattern of TET2 upregulation stood out as the most consistent finding linked to the genetic signal.

With TET2 identified as the prime suspect, the researchers moved to mechanistic experiments to determine how the gene is controlled during inflammation. When monocytes were exposed to inflammatory stimulation with lipopolysaccharide, levels of the m6A demethylase ALKBH5 rose. This enzyme chemically removes m6A marks from target messenger RNAs. The team found that inflammatory induction of ALKBH5 led to a reduction in m6A modification of TET2 messenger RNA, which in turn increased TET2 protein levels. Using m6A RNA immunoprecipitation to quantify the modification directly, they confirmed that the m6A mark on TET2 transcript was diminished in the presence of ALKBH5, and that wild-type ALKBH5, but not a demethylase-deficient mutant, produced this effect. The result establishes a concrete regulatory loop: inflammation induces ALKBH5, ALKBH5 strips m6A from TET2 messenger RNA, and more TET2 protein accumulates in the cell.

The downstream consequences were equally clear. Elevated TET2 protein activated PI3K/AKT signaling, measurable by increased levels of phosphorylated AKT, and boosted production of pro-inflammatory cytokines, the chemical messengers that recruit and intensify immune responses in the airways. Crucially, the researchers showed that interrupting the pathway at either end, by knocking down TET2 with small interfering RNA or by suppressing ALKBH5, attenuated both the signaling activation and the cytokine output. These loss-of-function experiments provide the strongest evidence yet that the ALKBH5-m6A-TET2 axis is not merely correlated with monocyte inflammation but is functionally required for it.

The implications of the study reach in several directions at once. For asthma genetics, it offers a concrete example of how a non-coding variant can exert its influence by altering an epitranscriptomic modification site rather than a protein-coding sequence, a mechanism that could explain a meaningful share of the missing heritability in asthma and other immune diseases. For immunology, it adds asthma to the growing list of inflammatory conditions in which RNA methylation dynamically reprograms innate immune cells, and it situates TET2, already famous for its roles in leukemia, cardiovascular disease, and clonal hematopoiesis, at the center of a respiratory inflammatory pathway. The involvement of monocytes is particularly relevant to patients with severe or neutrophilic asthma, in whom steroid responses are often poor and innate immune cells are thought to drive much of the disease burden.

Most tantalizing is the therapeutic possibility. Because ALKBH5 acts upstream of TET2 in this pathway, inhibiting ALKBH5 could, in principle, restore m6A marks on TET2 messenger RNA, reduce TET2 protein levels, and calm the overactive PI3K/AKT-driven inflammatory program in monocytes without broadly suppressing the immune system. The authors caution that their findings rest on genetic association, single-cell profiling, and cell-culture experiments, and that validation in patient samples and animal models will be needed before the ALKBH5-m6A-TET2 axis can be considered a drug target. Nevertheless, the study provides a complete narrative arc, from a population-level genetic signal to a molecular mechanism inside individual immune cells, and it does so with an analytical strategy that other researchers can apply to the many complex diseases whose genetics remain stubbornly unexplained. As the cost of single-cell sequencing falls and catalogs of RNA modification sites continue to expand, the approach demonstrated here is likely to be repeated across a widening range of conditions, potentially converting thousands of obscure genetic associations into actionable biological insights.

Subject of Research: Epitranscriptomic regulation of monocyte inflammatory activation in asthma via the ALKBH5-m6A-TET2 axis and PI3K signaling

Article Title: TET2 promotes monocyte inflammatory activation in asthma via ALKBH5-m6A regulation and PI3K signaling: evidence from m6A-SNP and single-cell analyses

Article References: Wang, Z., Wang, Q., Sa, Y., Ma, N., Wang, S., Huang, C., Liu, M., & Tang, S. (2026). TET2 promotes monocyte inflammatory activation in asthma via ALKBH5-m6A regulation and PI3K signaling: evidence from m6A-SNP and single-cell analyses. Molecular Genetics and Genomics, 301(1), Article 190. https://doi.org/10.1007/s00438-026-02497-x

Image Credits: AI Generated

DOI: 10.1007/s00438-026-02497-x

Keywords: asthma, TET2, ALKBH5, m6A modification, monocytes, PI3K/AKT signaling, GWAS, m6A-SNP, single-cell RNA sequencing, airway inflammation, epitranscriptomics, genetic susceptibility