Tet2-mediated epigenetic modifications during aging of hematopoietic stem and progenitor cells
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE157592 | GEO | 2023/09/10
REPOSITORIES: GEO
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Project description:we compared self-renewal and lineage specification of WT and Tet2-deficient HSPCs during ageing and demonstrated that Tet2 ablation alters age-dependent HSC functional decline, revealing a disparate ageing process in the Tet2-deficient haemopoietic system.
2023-08-11 | GSE183675 | GEO
Project description:Loss of function TET2 mutations are frequently seen in myelodysplastic syndrome (MDS) patients. Previous studies have demonstrated that TET2 deficiency enhances maintenance of MDS hematopoietic stem and progenitor cells (HSPCs). Nonetheless, the pathogenic role of TET2 in MDS progression remains elusive. Here, we demonstrate Tet2 knockout (KO) markedly accelerated malignant transformation in Nup98-HoxD13 (NHD13) transgenic mice and promotes leukemogenesis of HoxA9 transduction/transplant mice. Consistently, low TET2 level cooperating with high HOXA9 level predicts poor outcome of MDS patients. Notably, Tet2 KO conferred a clonal advantage to the HSPCs of NHD13 mice. Whole-exome sequencing revealed that Tet2 KO facilitates accumulation of mutations at genes associated with leukemogenesis, including Arih2, whose loss of function promotes MDS cells proliferation. Using 5-hydroxymethylcytosine immunoprecipitation coupled with high-throughput sequencing analysis, we found while Tet2 deletion decreased overall 5hmC levels, it also increased 5hmC distribution at certain mutation loci such as Arih2. Vitamin C treatment, which mimics Tet2/Tet3 restoration, blocked disease progression in Tet2-deficient NHD13 mice. Collectively, our findings demonstrate that TET2 activity governs occurrence of secondary mutations in MDS HSPCs, providing a rationale for enhancing TETs function to block MDS-malignant transformation.
2022-10-12 | GSE213591 | GEO
Project description:Loss of function TET2 mutations are frequently seen in myelodysplastic syndrome (MDS) patients. Previous studies have demonstrated that TET2 deficiency enhances maintenance of MDS hematopoietic stem and progenitor cells (HSPCs). Nonetheless, the pathogenic role of TET2 in MDS progression remains elusive. Here, we demonstrate Tet2 knockout (KO) markedly accelerated malignant transformation in Nup98-HoxD13 (NHD13) transgenic mice and promotes leukemogenesis of HoxA9 transduction/transplant mice. Consistently, low TET2 level cooperating with high HOXA9 level predicts poor outcome of MDS patients. Notably, Tet2 KO conferred a clonal advantage to the HSPCs of NHD13 mice. Whole-exome sequencing revealed that Tet2 KO facilitates accumulation of mutations at genes associated with leukemogenesis, including Arih2, whose loss of function promotes MDS cells proliferation. Using 5-hydroxymethylcytosine immunoprecipitation coupled with high-throughput sequencing analysis, we found while Tet2 deletion decreased overall 5hmC levels, it also increased 5hmC distribution at certain mutation loci such as Arih2. Vitamin C treatment, which mimics Tet2/Tet3 restoration, blocked disease progression in Tet2-deficient NHD13 mice. Collectively, our findings demonstrate that TET2 activity governs occurrence of secondary mutations in MDS HSPCs, providing a rationale for enhancing TETs function to block MDS-malignant transformation.
2022-10-12 | GSE213530 | 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:To identify genes that are influenced by the catalytic and non-catalytic functions of Tet2 in hematopoietic stem and progenitor cells (HSPCs), we analyzed the gene expression profiles of Tet2 catalytic mutant (Tet2 Mut), Tet2 knockout (Tet2 KO) and wild-type HSPCs (or LSK, Lin–Sca-1+c-Kit+) and multi-potent progenitor (or MPP, Lin–) cells by RNA-seq.
2019-08-05 | GSE132090 | GEO
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:Ageing is associated with changes in the cellular composition of the immune system. During ageing, hematopoietic stem and progenitor cells (HSPCs) that produce immune cells are thought to decline in their regenerative capacity. However, HSPC function has been mostly assessed using transplantation assays, and it remains unclear how HSPCs age in the native bone marrow niche. To address this issue, we present a novel in situ single cell lineage tracing technology to quantify the clonal composition and cell production of single cells in their native niche. Our results demonstrate that a pool of HSPCs with unequal output maintains myelopoiesis through overlapping waves of cell production throughout adult life. During ageing, the increased frequency of myeloid cells is explained by greater numbers of HSPCs contributing to myelopoiesis, rather than increased myeloid output of individual HSPCs. Strikingly, the myeloid output of HSPCs remained remains constant over time despite accumulating significant transcriptomic changes throughout adulthood. Together, these results show that, unlike emergency myelopoiesis post-transplantation, aged HSPCs in their native microenvironment do not functionally decline in their regenerative capacity. This repository contains single-cell RNA sequencing datasets of hematopoietic stem and progenitor cells from young and aged mice associated with this study
2023-02-27 | GSE226131 | GEO
Project description:TET2 plays an important role in regulating the behavior of bone marrow derived MSCs in addition to its intrinsic role in HSPCs to participate in aberrant hematopoiesis. Moreover, MSCs are the most important niche cell components in Tet2-/- mice that contribute to the progression of Tet2 deletion-driven myeloid malignancies. This SuperSeries is composed of the SubSeries listed below.
2018-02-13 | GSE100073 | GEO
Project description:The conversion of 5-methylcytosine (5mC) into 5-Hydroxymethylcytosine (5hmC) by ten-eleven translocation (Tet) family has recently been identified as a key process for active DNA demethylation, whose effects in the immune response is currently unknown. We used microarrays to characterize the regulation of Tet2 in T cells. We found that deletion of the Tet2 gene in T cells decreased expression of effector cytokines such as IFN-?, IL-17, and IL-10. To analyze the regulation of Tet2 in Th subset differentation, CD2(Cre)Tet2(f/f) mice were used to derive Tet2-deficient Th1 and Th17 cells, and Tet2(f/f) mice were used for Tet2-enriched Th1 and Th17 cells.
2015-04-12 | E-GEOD-48657 | biostudies-arrayexpress
Project description:TET2 is one of the most frequently mutated genes in hematological malignancies. TET2 mutations are also frequently observed in healthy individuals with clonal hematopoiesis. Additional factors, such as inflammatory stress, might promote the expansion and initiate the pre-leukemic condition of Tet2 deficient hematopoietic stem cells. Antibiotics treatment is frequently used in normal individuals and patients with hematological malignancies treatment to suppress infection-induced inflammation. However, prolonged antibiotics treatment resulted in bone marrow suppression and gut microbiota alteration. In our study, we observed that the expansion of Tet2 deficient myeloid cells are positively correlated with serum cytokine levels at pre-malignant stages. We then evaluated the effect of antibiotic treatment in Tet2 deficient myeloid and lymphoid tumors in vivo. We found that antibiotics treatment suppressed the growth of Tet2 deficient malignant cells in vivo. RNA-seq analysis revealed significant changes in immune related signaling pathways (e.g., Tnf-α signaling) in antibiotics treated Tet2 deficient myeloid and lymphoid tumor cells. Suppression of Tnf-α signaling using pharmacological inhibitors partially suppressed Tet2 deficient tumor cell growth in vivo. In summary, our results suggest that the expansion of Tet2 deficient blood cells are positively associated with a pre-inflammatory condition and suppression of inflammatory pathways may attenuate the progression of TET2 inactivation-associated hematological malignancies.
2021-04-01 | GSE129886 | GEO