TET2-mutant clonal hematopoiesis and risk of gout
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ABSTRACT:
PROVIDER: PRJNA848666 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19634367_1.fastq.gz | Fastqsanger.gz | |||
| SRR19634367_2.fastq.gz | Fastqsanger.gz | |||
| SRR19634368_1.fastq.gz | Fastqsanger.gz | |||
| SRR19634368_2.fastq.gz | Fastqsanger.gz | |||
| SRR19634369_1.fastq.gz | Fastqsanger.gz |
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Project description:Gout is a common inflammatory arthritis caused by precipitation of monosodium urate (MSU) crystals in individuals with hyperuricemia. Acute flares are accompanied by secretion of pro-inflammatory cytokines, including interleukin-1 beta (IL-1B). Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition predisposing to hematologic cancers and cardiovascular disease. CHIP is associated with elevated IL-1B, thus we investigated CHIP as a risk factor for gout. To test the clinical association between CHIP and gout, we analyzed whole exome sequencing data from 177,824 individuals in the MGB Biobank (MGBB) and UK Biobank (UKB). In both cohorts, the frequency of gout was higher among individuals with CHIP than without CHIP (MGBB, CHIP with variant allele fraction [VAF] ≥2%: OR, 1.69; 95% CI, 1.09-2.61; P=0.0189; UKB, CHIP with VAF ≥10%: OR, 1.25; 95% CI, 1.05-1.50; P=0.0133). Moreover, individuals with CHIP and a VAF ≥10% had an increased risk of incident gout (UKB: HR, 1.28; 95% CI, 1.06-1.55; P=0.0107). In murine models of gout pathogenesis, animals with Tet2 knockout hematopoietic cells had exaggerated IL-1B secretion and paw edema upon administration of MSU crystals. Tet2 knockout macrophages elaborated higher levels of IL-1B in response to MSU crystals in vitro, and this was ameliorated through genetic and pharmacologic Nlrp3 inflammasome inhibition. These studies show that TET2-mutant CHIP is associated with an increased risk of gout in humans and that MSU crystals lead to elevated IL-1B levels in Tet2 knockout murine models. We identify CHIP as an amplifier of NLRP3-dependent inflammatory responses to MSU crystals in gout patients.
2022-06-14 | GSE205963 | GEO
Project description:Clonal hematopoiesis of indeterminate potential is prevalent in elderly individuals and associated with increased risks of all-cause mortality and cardiovascular disease. However, mouse models to study the dynamics of clonal hematopoiesis and its consequences on the cardiovascular system under homeostatic conditions are lacking. We used a model of clonal hematopoiesis using adoptive transfer of unfractionated ten-eleven translocation 2-mutant (Tet2-mutant) bone marrow cells into nonirradiated mice. Consistent with age-related clonal hematopoiesis observed in humans, these mice displayed a progressive expansion of Tet2-deficient cells in multiple hematopoietic stem and progenitor cell fractions and blood cell lineages. The expansion of the Tet2-mutant fraction was also observed in bone marrow-derived CCR+ myeloid cell populations within the heart, but there was a negligible impact on the yolk sac-derived CCR2- cardiac resident macrophage population. Transcriptome profiling revealed an enhanced inflammatory signature in the donor-derived macrophages isolated from the heart. Mice receiving Tet2-deficient bone marrow cells spontaneously developed age-related cardiac dysfunction characterized by greater hypertrophy and fibrosis. Altogether, we show that Tet2- mediated hematopoiesis contributes to cardiac dysfunction in a nonconditioned setting that faithfully models the human clonal hematopoiesis in unperturbed bone marrow. Our data support clinical findings that clonal hematopoiesis per se may contribute to diminished health span.
2020-03-12 | GSE146812 | GEO
Project description:Gout is a common inflammatory arthritis caused by precipitation of monosodium urate (MSU) crystals in individuals with hyperuricemia. Acute flares are accompanied by secretion of proinflammatory cytokines, including interleukin-1β (IL-1β). Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition predisposing to hematologic cancers and cardiovascular disease. CHIP is associated with elevated IL-1β, thus we investigated CHIP as a risk factor for gout. To test the clinical association between CHIP and gout, we analyzed whole exome sequencing data from 177 824 individuals in the MGB Biobank (MGBB) and UK Biobank (UKB). In both cohorts, the frequency of gout was higher among individuals with CHIP than without CHIP (MGBB, CHIP with variant allele fraction [VAF] ≥2%: odds ratio [OR], 1.69; 95% CI, 1.09-2.61; P = .0189; UKB, CHIP with VAF ≥10%: OR, 1.25; 95% CI, 1.05-1.50; P = .0133). Moreover, individuals with CHIP and a VAF ≥10% had an increased risk of incident gout (UKB: hazard ratio [HR], 1.28; 95% CI, 1.06-1.55; P = .0107). In murine models of gout pathogenesis, animals with Tet2 knockout hematopoietic cells had exaggerated IL-1β secretion and paw edema upon administration of MSU crystals. Tet2 knockout macrophages elaborated higher levels of IL-1β in response to MSU crystals in vitro, which was ameliorated through genetic and pharmacologic Nlrp3 inflammasome inhibition. These studies show that TET2-mutant CHIP is associated with an increased risk of gout in humans and that MSU crystals lead to elevated IL-1β levels in Tet2 knockout murine models. We identify CHIP as an amplifier of NLRP3-dependent inflammatory responses to MSU crystals in patients with gout.
| S-EPMC9461470 | biostudies-literature
Project description:To investigate the signaling pathway required for the Tet2 mutant associated clonal hematopoiesis, we identified the activated signaling pathway in Tet2-deficient hematopoietic stem/progenitor cells compared to WT cells and using transgentic mouse model to validate our findings. In short, the cGAS-STING pathway is activated in Tet2-deficient HSPCs and promotes the development of CH associated with Tet2 deficiency.
2023-05-15 | GSE232384 | GEO
Project description:The expansion of HSC clones and their immune progeny carrying somatic mutations is defined as clonal hematopoiesis (CH) with its prevalence increasing with age. Individuals with CH are at higher risk of developing hematological malignancies but also other pathologies, such as cardiovascular or inflammatory pulmonary diseases. Understanding which environmental conditions favor mutant clones and the CH-immune system response to such environments is key to designing therapeutic strategies to stall the expansion of mutant clones and the development of CH-associated pathologies. In this work, we characterized how mutations in TET2, one of the most frequent in CH, increase the competitive advantage of human HSCs upon environmental stress conditions and at the same time shape the immune response of their myeloid progeny. Employing a humanized mouse model, we show that environmental conditions that drive emergency myelopoiesis promote human TET2-derived CH. We unravel an opposite and cell-specific impact of TET2 mutations on HSCs and their myeloid progeny to inflammatory stress. In such environments, TET2Mut HSCs have a mitigated transcriptional upregulation of inflammatory pathways, and by contrast, TET2Mut myeloid cells have an exacerbated inflammatory response. A distinct monocyte-macrophage trajectory derived from TET2Mut HSCs contributes to pathological inflammation. These findings provide evidence at the human cell level and reconcile the notion that TET2-derived CH is associated with both increased stemness at the HSC compartment and promoted inflammatory environments from the myeloid progeny.
2025-10-29 | GSE285379 | GEO
Project description:Recent work has revealed that clonal hematopoiesis (CH) is associated with a higher risk of numerous age-related diseases, including ischemic stroke, however little is known about whether it influences stroke outcome. Studies suggest that leukocytes carrying CH driver mutations have an enhanced inflammatory profile, which could conceivably exacerbate brain injury after a stroke. Using a mouse model of Tet2-mediated CH, we tested the hypothesis that CH would lead to a poorer outcome after ischemic stroke by augmenting brain inflammation. In contrast to our hypothesis, Tet2-mediated CH had no effect on acute stroke outcome but led to reduced neurological deficits during the subacute phase. This improved neurological outcome was associated with lower levels of brain inflammation during this time, suggesting that Tet2-mediated CH may promote inflammation resolution in the brain post-stroke. While additional mechanistic studies are required, these findings may suggest that Tet2-mediated CH has beneficial actions on the post-stroke brain.
2025-01-08 | GSE270710 | GEO
Project description:TET2 is among the most commonly mutated genes in both clonal hematopoiesis and myeloid malignancies, thus, the ability to identify selective dependencies in TET2 deficient cells has broad translational significance. Here, we identify regulators of Tet2 knockout (KO) hematopoietic stem and progenitor cell (HSPC) expansion using an in vivo CRISPR-Cas9 KO screen, in which nucleotide barcoding enabled large-scale clonal tracing of Tet2 deficient HSPCs in a physiological setting. Our screen identified candidate genes, including Ncoa4, that are selectively required for Tet2 KO clonal outgrowth compared to wild-type (WT). Ncoa4 targets ferritin for lysosomal degradation (ferritinophagy), maintaining intracellular iron homeostasis by releasing labile iron (Fe2+) in response to cellular demands. In Tet2-deficient HSPCs, increased mitochondrial ATP production correlates with increased cellular iron requirements, and in turn, promotes Ncoa4-dependent ferritinophagy. Restricting iron availability reduces Tet2 KO stem cell numbers, revealing a dependency in TET2-mutated myeloid neoplasms.
2025-06-01 | GSE289732 | GEO
Project description:Hematopoietic malignancies emerge through the gradual acquisition of genetic mutations within hematopoietic stem and progenitor cells (HSPCs). Mutations that occur early in disease progression impart a selective growth advantage to HSPCs, which allows them to expand and contribute to a substantial percentage of mature blood cells. This increased expansion is termed clonal hematopoiesis (CH) and is a preleukemic phase associated with an increased risk of developing leukemia. Inhibitor of DNA binding 1 (ID1) protein is a transcriptional regulator of proliferation/differentiation of neuronal, muscle, and other cells, and is frequently overexpressed in cancer. Id1 is expressed at low levels in normal HSCs and is induced by growth factors and other mediators of inflammatory stress and promotes HSPC proliferation. HSCs that lack Id1 (Id1-/-) show reduced cycling/activation and are protected from exhaustion under chronic stress including bone marrow transplantation (BMT), genotoxic and inflammatory stress, and aging. Since chronic inflammation is associated with the progression of hematopoietic malignancies, reducing Id1 expression during CH may be therapeutic. Mutations in TET2 are frequently observed in patients with CH, and Tet2-/- mice show CH. ID1 is upregulated in HSPCs from patients with TET2 mutations and Tet2-/- mice. Genetic ablation of Id1 in Tet2-/- HSPCs reduces HSPC expansion/self-renewal/CH, extramedullary hematopoiesis, myeloid skewing, genetic instability and delays the onset of disease. Mechanistically, p16 expression, senescence and apoptosis were increased and proliferation decreased in Tet2-/-; Id1-/- HSPCs. Thus, ID1 may represent a potential therapeutic target to reduce CH and delay the onset of leukemia.
2025-05-03 | GSE266580 | GEO
Project description:The opposing effect of TET2-derived clonal hematopoiesis in stemness and immunity
| PRJNA1203250 | ENA
Project description:Tet2-mediated clonal hematopoiesis in nonconditioned mice accelerates age-associated cardiac dysfunction
| PRJNA612022 | ENA