Mus musculus strain:C57BL/6J
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1065362 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27563745_1.fastq.gz | Fastqsanger.gz | |||
| SRR27563745_2.fastq.gz | Fastqsanger.gz | |||
| SRR27563746_1.fastq.gz | Fastqsanger.gz | |||
| SRR27563746_2.fastq.gz | Fastqsanger.gz | |||
| SRR27563747_1.fastq.gz | Fastqsanger.gz |
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Project description:<p>Hematopoietic stem cell (HSC) mutations can result in clonal hematopoiesis (CH) with heterogeneous clinical outcomes. Here, we investigated how the cell state preceding <em>Tet2</em> mutation impacts the pre-malignant phenotype. Using an inducible system for clonal analysis of myeloid progenitors, we found that the epigenetic features of clones at similar differentiation status were highly heterogeneous and functionally responded differently to <em>Tet2</em> mutation. Cell differentiation stage also influenced <em>Tet2</em> mutation response indicating that the cell of origin's epigenome modulates clone-specific behaviors in CH. Molecular features associated with higher risk outcomes include <em>Sox4</em> that sensitized cells to <em>Tet2</em> inactivation, inducing dedifferentiation, altered metabolism and increasing the <em>in vivo</em> clonal output of mutant cells, as confirmed in primary GMP and HSC models. Our findings validate the hypothesis that epigenetic features can predispose specific clones for dominance, explaining why identical genetic mutations can result in different phenotypes.</p>
1970-01-01 | MTBLS9914 | MetaboLights
Project description:The TET2 gene encodes an α-ketoglutarate-dependent dioxygenase able to oxidize 5-methylcytosine into 5-hydroxymethylcytosine, which is a step toward active DNA demethylation. TET2 is frequently mutated in myeloid malignancies but also in B- and T-cell malignancies. TET2 somatic mutations are also identified in healthy elderly individuals with clonal hematopoiesis. Tet2-deficient mouse models showed widespread hematological differentiation abnormalities, including myeloid, T-cell, and B-cell malignancies. We show here that, similar to what is observed with constitutive Tet2-deficient mice, B-cell-specific Tet2 knockout leads to abnormalities in the B1-cell subset and a development of B-cell malignancies after long latency. Aging Tet2-deficient mice accumulate clonal CD19+ B220low immunoglobulin M+ B-cell populations with transplantable ability showing similarities to human chronic lymphocytic leukemia, including CD5 expression and sensitivity to ibrutinib-mediated B-cell receptor (BCR) signaling inhibition. Exome sequencing of Tet2-/- malignant B cells reveals C-to-T and G-to-A mutations that lie within single-stranded DNA-specific activation-induced deaminase (AID)/APOBEC (apolipoprotein B messenger RNA editing enzyme, catalytic polypeptide-like) cytidine deaminases targeted motif, as confirmed by the lack of a B-cell tumor in compound Tet2-Aicda-deficient mice. Finally, we show that Tet2 deficiency accelerates and exacerbates T-cell leukemia/lymphoma 1A-induced leukemogenesis. Together, our data establish that Tet2 deficiency predisposes to mature B-cell malignancies, which development might be attributed in part to AID-mediated accumulating mutations and BCR-mediated signaling. This accession concerns 46 transcriptomic experiments with Affymetrix Mouse 430-2 array..
2019-12-12 | E-MTAB-8501 | biostudies-arrayexpress
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:Somatic mutation in TET2 gene is one of the most common clonal genetic events detected in age-related clonal hematopoiesis as well as in chronic myelomonocytic leukemia (CMML). In addition to being a pre-malignant state, TET2 mutated clones are associated with an increased risk of death from cardiovascular disease, which could involve cytokine/chemokine overproduction by monocytic cells. Here, we show in mice and in human cells that, in the absence of any inflammatory challenge, TET2 down-regulation promotes the production of MIF (macrophage migration inhibitory factor), a pivotal mediator of atherosclerotic lesion formation. In healthy monocytes, TET2 is recruited to MIF promoter and interacts with the transcription factor EGR1 and histone deacetylases. Disruption of these interactions as a consequence of TET2-decreased expression favors EGR1-driven transcription of MIF gene and its secretion. MIF favors monocytic differentiation of myeloid progenitors. These results designate MIF as a chronically overproduced chemokine and a potential therapeutic target in patients with clonal TET2 down-regulation in myeloid cells.
2021-11-13 | GSE188624 | GEO
Project description:Gene expression profile of individual CFU-GM colonies identified as uniallelic TET2 mutant versus TET2 wild type was analyzed via RNA-Seq to verify the impact of TET2 editing on gene expression in the rhesus macaque clonal hematopoiesis model.
2022-06-22 | GSE148132 | GEO
Project description:TET2-mutant clonal hematopoiesis and risk of gout
| PRJNA848666 | ENA
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:Loss of function mutations inTET2(LOF) occur in up to 58% and 30% of myeloid malignancies and clonal hematopoiesis (CH) respectively. Genetically engineered murine models of Tet2 LOF display splenomegaly, granulomonocytic expansion, and increased bone marrow hematopoietic stem and progenitors. However, the direct downstream effectors of TET2 LOF leading to this phenotype are unknown. Using multiome single cell sequencing from a cohort of severe COVID patients with or without TET2 mutations we show that MALAT1, a therapeutically tractable long non-coding RNA, is overexpressed and is both necessary and sufficient to induce TET2 LOF phenotypes. We additionally demonstrate that TET2 LOF leads to decrease activity of the transcriptional repressor EGR1 leading to upregulation of MALAT1. This upregulation then leads to sustained NFkB activity by inhibiting the phosphatase activity of PP2A on P65 resulting in increased pro-inflammatory cytokines such as IL-6 required for TET2 LOF phenotypes in MALAT1 overexpressing mice
2024-08-13 | GSE243492 | GEO
Project description:Somatic mutations acquired by hematopoietic stem cells (HSCs) are commonly found over the course of a lifespan. Some of these clones will outgrow through a process known as clonal hematopoiesis (CH) and produce mutated immune cell progeny, which will shape host immunity. Individuals with CH are asymptomatic but have increased risk of developing leukemia, cardiovascular and pulmonary inflammatory diseases, and severe infections. Despite the key role that neutrophils play in the development of such diseases, little is known about how these prevalent somatic mutations affect neutrophil functionality. In this work, we describe how mutations in TET2, one of the most common mutated genes in individuals with CH, affect human neutrophil biology.
2023-06-05 | GSE228077 | GEO
Project description:Somatic mutations acquired by hematopoietic stem cells (HSCs) are commonly found over the course of a lifespan. Some of these clones will outgrow through a process known as clonal hematopoiesis (CH) and produce mutated immune cell progeny, which will shape host immunity. Individuals with CH are asymptomatic but have increased risk of developing leukemia, cardiovascular and pulmonary inflammatory diseases, and severe infections. Despite the key role that neutrophils play in the development of such diseases, little is known about how these prevalent somatic mutations affect neutrophil functionality. In this work, we describe how mutations in TET2, one of the most common mutated genes in individuals with CH, affect human neutrophil biology.
2023-12-01 | GSE213769 | GEO