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TET2-mutant clonal hematopoiesis prevents T-cell exhaustion and suppresses cancer metastasis [scRNA-seq]

ABSTRACT: TET2-mutant clonal hematopoiesis (CH) is associated with reduced cancer metastasis in human cohorts. Using mouse models of colorectal cancer liver metastasis, we demonstrate that Tet2-deficient hematopoietic cells suppress metastatic tumor burden by preventing CD8+ T-cell exhaustion. Single-cell RNA-seq with paired V(D)J T-cell receptor (TCR) sequencing of CD45+ tumor-infiltrating leukocytes from Vav1CreTet2KO and Tet2fl/fl mice was performed to characterize transcriptional and clonotypic changes associated with TET2 loss in tumor-infiltrating immune cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE327649 | GEO | 2026/04/17

REPOSITORIES: GEO

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TET2-mutant clonal hematopoiesis prevents T-cell exhaustion and suppresses cancer metastasis [RNA-seq]

Project description:TET2-mutant clonal hematopoiesis (CH) is associated with reduced cancer metastasis in human cohorts. Using mouse models of colorectal cancer liver metastasis, we demonstrate that Tet2-deficient hematopoietic cells suppress metastatic tumor burden by preventing CD8+ T-cell exhaustion. Bulk RNA-seq of sorted CD4+ and CD8+ tumor-infiltrating lymphocytes (TILs) from Vav1CreTet2KO, Cd4CreTet2KO, and Tet2fl/fl control mice was performed to characterize transcriptional changes associated with Tet2 loss in tumor-infiltrating T cells.

2026-04-17 | GSE327454 | GEO

TET2-mutant clonal hematopoiesis prevents T-cell exhaustion and suppresses cancer metastasis

Project description:TET2-mutant clonal hematopoiesis (CH) is associated with reduced cancer metastasis in human cohorts. Whole genome bisulfite sequencing (WGBS) of PD-1+CD8+ tumor-infiltrating lymphocytes (TILs) sorted from liver metastatic tumors of Vav1CreTet2KO and Tet2fl/fl mice was performed to characterize genome-wide DNA methylation changes associated with TET2 loss in exhausted CD8+ T cells.

2026-04-17 | GSE327756 | GEO

Hematopoietic Tet2 inactivation enhances the response to checkpoint blockade immunotherapy

Project description:Somatic mutations inactivating TET2 are among the most common drivers of clonal hematopoiesis (CH). While TET2 inactivation is associated with monocyte-derived inflammation and improved chimeric antigen-receptor-T cell function, its impact on immunotherapy response is unknown. In murine models, hematopoietic Tet2 mutation enhanced the immune checkpoint blockade (ICB) response via the combined presence of phagocytes, CD4 and CD8 T cells. Mechanistically, in Tet2-mutant tumor-infiltrating leukocytes (TILs), ICB preferentially restricted cell states linked to tumor progression while inducing anti-tumor states. Tet2-mutant monocytes activated costimulatory programs, while Tet2-mutant T cells showed enhanced T cell memory signatures, alongside decreased exhaustion and regulatory phenotypes. This murine data was clinically relevant, since tumors from colorectal cancer and melanoma patients with TET2 driver mutation-CH (TET2-CH) showed enhanced immune infiltration, inflammation, and T cell activation. In melanoma patients treated with ICB, TET2-CH was associated with 6-fold greater odds of clinical benefit. Collectively, our data establishes that hematopoietic Tet2 inactivation primes leukocytes for anti-tumor states associated with immunotherapy response and provides a potential biomarker for personalized therapy.

2025-10-01 | GSE307901 | GEO

The opposing effect of TET2-derived clonal hematopoiesis in stemness and immunity

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

Tet2-mediated clonal hematopoiesis improves neurological deficits and is associated with inflammation resolution in the subacute phase of stroke

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

Identify the key signaling pathway involved in the Tet2 deficiency-induced clonal hematopoiesis

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

B12 promotes gut dysbiosis and an inflammatory microenvironment that potentiates myeloid biased Tet2-deficient hematopoiesis [dataset 2]

Project description:Recent studies have linked elevated vitamin B12 serum levels with the presence of Clonal Hematopoiesis (CH) and an increased risk of developing myeloid malignancy. High B12 supplementation increases serum levels, alters gut microbial composition, and reduces the production of short-chain fatty acids (SCFAs), which help maintain gut barrier function and mucosal integrity. TET2 mutation is a frequent driver of CH that progresses in a positive feedback loop in response to microbial signals suggesting that B12 may influence CH via the gut microbiome. We evaluated the microenvironmental effects of B12 supplementation in a Tet2-deficient model of CH and found that B12 enhances myelopoiesis, heightens the responses of myeloid cells to bacterial stimuli, and increases the levels of circulating inflammatory cytokines. B12 supplementation also induced gut dysbiosis and reduced the levels of SCFA-producing bacteria in both wild-type and Tet2-deficient mice. Importantly, the effects of excess B12 were reversible upon oral supplementation with the SCFA butyrate. These findings suggest that B12 may promote CH progression by disrupting microbiome-derived SCFA metabolism, highlighting a potential therapeutic role for SCFA supplementation in mitigating CH.

2026-04-13 | GSE306039 | GEO

B12 promotes gut dysbiosis and an inflammatory microenvironment that potentiates myeloid biased Tet2-deficient hematopoiesis [dataset 1]

2026-04-13 | GSE269659 | GEO

Ablation of Id1 Reduces Clonal Hematopoiesis, Genomic Instability and Delays Leukemia in Mice with Tet2 Loss of Function [RNA-seq]

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

Effect of endothelial cell-specific TET2 knockout on mouse lung endothelial cell transcriptome of chow-fed and high fat diet-fed mice

Project description:RNA sequencing of mouse lung endothelial cells from male wildtype (TET2fl/fl Cre negative, tamoxifen-injected) or endothelial-specific TET2 knockout mice (TET2fl/fl, Cdh5-CreERT2 positive, tamoxifen-injected) fed either a standard chow diet or a high fat diet for 20 weeks.

2025-07-23 | GSE232888 | GEO

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