TET2-mutant clonal hematopoiesis prevents T-cell exhaustion and suppresses cancer metastasis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE327756 | GEO | 2026/04/17
REPOSITORIES: GEO
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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
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. 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.
2026-04-17 | GSE327649 | 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: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: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
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: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:Somatic mutations that cause the clonal outgrowth of mutant hematopoietic stem cells (HSCs), known as clonal hematopoiesis (CH), decay myeloid heterogeneity, activate inflammation, and increase the risk of atherosclerosis. However, whether lifestyle alters myeloid cell diversity by either modulating CH clone expansion or the phenotypic programming of CH mutant cells, thereby impacting atherosclerosis, is unknown. Here, in humans and mice and across mutations in Jak2, Tet2, p53 and Dnmt3a, we demonstrate mutation-dependent responses to lifestyle in CH and show that mutant cells are uniquely and selectively sensitive to lifestyle exposures. Sleep and exercise restrict Jak2 and Tet2 CH and its atherogenic consequences by diminishing the clonal expansion of mutant HSCs and reprogramming mutant bone marrow (BM) HSCs and aortic macrophages, but not their neighboring wildtype (WT) counterparts, through divergent brain-body axes. In two large human datasets, moderate-to-vigorous physical associated with less non-DNMT3A CH. In atherogenic mice with Jak2 or Tet2 but not p53 or Dnmt3a CH, uninterrupted sleep or exercise curtails clone expansion. In Jak2 CH sleep and exercise do so by selectively reprogramming mutant, but not WT, BM HSCs towards anti-proliferative and metabolically healthy phenotypes by tempering BM macrophage-HSC IL-1β signaling. Sleep or exercise also lessens Jak2-, Tet2-, and p53-, but not Dnmt3a-, driven atherosclerosis, partly independent of BM clonal dynamics, by locally reprogramming mutant macrophages in atherosclerotic lesions. In Jak2 mutant, but not adjacent WT, aortic macrophages, uninterrupted sleep reduces cell death, selectively blunting CLEC4E-dependent inflammasome activation and IL-1β generation, consequently diminishing lesions. Exercise, meanwhile, activates PAC1+ neurons in the brain’s locus coeruleus (LC), raising peripheral norepinephrine (NE), and preserves the expression of NE’s adrenergic receptor (ADR) β2 in Jak2V617F, but not cohabitant WT, aortic macrophages. Exercise-mediated NE signaling from the brain’s LC to Jak2V617F aortic macrophages selectively represses their inflammatory programing and atherosclerosis. Together, our findings uncover gene-lifestyle coaction and establish that healthy lifestyles gene-specifically diminish CH and selectively reprogram mutant HSCs and macrophages to maintain myeloid heterogeneity and cardiovascular health.
2026-04-06 | GSE317642 | GEO
Project description:CD8+ T cells isolated from HCC tissue were divided into three groups: PD1-TIM3- CD8+ TILs, exhibiting full effector function; PD1-intTIM3+ CD8+ TILs, exhibiting partial exhaustion; and PD1-hiTIM3+ CD8+ TILs, exhibiting severe exhaustion, as reflected by the differences in their ability to produce effector cytokines respectively. Transcriptome sequence analysis was performed to investigate the gene expression profile was performed.
2019-12-31 | E-MTAB-7278 | biostudies-arrayexpress
Project description:Inactivation of tumor infiltrating lymphocytes (TILs) is one of the limiting factors of anti-tumor immunity during tumor onset and progression. Epigenetic abnormalities are regarded as a major culprit contributing to the dysfunction of TILs within tumor microenvironment. In this study, we used a murine model of melanoma to discover that Tet2 inactivation significantly enhances the anti-tumor activity of TILs, with the efficacy comparable to immune checkpoint inhibition imposed by anti-PD-L1 treatment. Single-cell RNA-seq analysis further reveals that Tet2-deficient TILs exhibit effector-like features. Transcriptomic and ATAC-seq analysis further demonstrated that Tet2 deletion reshapes the chromatin accessibility and favors the binding of transcription factors geared toward CD8+ T cell activation. In summary, our study establishes that Tet2 constitutes one of the epigenetic barriers contributing to dysfunction of TILs during anti-tumor immunity, and that Tet2 inactivation could benefit anti-tumor immunity and suppress tumor growth.
2021-04-20 | GSE152496 | GEO