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Tet2 and p53 cooperate to promote leukemia and modulate response to inflammation [Copy number]

ABSTRACT: TET2, a regulator of DNA methylation, is amongst the most commonly mutated genes in acute myeloid leukemia (AML) and is linked to enhanced inflammatory responses. The ability to respond to TP53 activation and inflammatory response has been linked to clonal advantage in hematopoietic stem-progenitors. These mutations combine and affect the pyroptosis pathway.

ORGANISM(S): Mus musculus

PROVIDER: GSE305288 | GEO | 2025/12/31

REPOSITORIES: GEO

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Tet2 and Tp53 cooperate to promote leukemia and modulate response to inflammation [Bisulfite-Seq]

Project description:TET2, a regulator of DNA methylation, is amongst the most commonly mutated genes in acute myeloid leukemia (AML) and is linked to enhanced inflammatory responses. The ability to respond to TP53 activation and inflammatory response has been linked to clonal advantage in hematopoietic stem-progenitors. These mutations combine and affect the pyroptosis pathway.

2025-12-31 | GSE300000 | GEO

Tet2 and p53 cooperate to promote leukemia and modulate response to inflammation [Copy number]

Project description:Tet2 and p53 cooperate to promote leukemia and modulate response to inflammation [Copy number]

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Myeloid TET2-IL-1 axis controls sympathetic-epithelial interaction to modulate intestinal inflammation

Project description:Inflammatory responses are mediated by complex multi-cellular interactions and understanding the identity and mechanism of these interactions is central to understanding the pathophysiology of immune-mediated diseases. In humans, somatic mutations in Tet methylcytosine dioxygenase 2 (TET2), a DNA demethylase, are commonly observed during ageing in myeloid cells1,2 and known to modulate inflammatory responses3. Using a mouse model that selectively lacks TET2 in myeloid cells, we show that myeloid cells and sympathetic neurons form a signaling nexus that controls the differentiation of enterochromaffin cells and serotonin production during colonic inflammation. Specifically, we demonstrate that TET2 restricts IL-1 production by myeloid cells under physiological conditions that in turn controls the intestinal sympathetic activation.

2025-07-08 | GSE267700 | GEO

14-3-3 protects AMPK phosphorylated TET2 from dephosphorylation by PP2A

Project description:Ten-eleven translocation-2 (TET2) is a member of the methylcytosine dioxygenase family of enzymes implicated in cancer and in aging due to its role as a global epigenetic modifier. TET2 has a large N-terminal domain followed by a catalytic C-terminal. Previous reports have demonstrated that the catalytic domain remains active independent of the N-terminal domain. As such, the function of the N-terminus of this large protein remains poorly characterized. Here, we identify that several isoforms of the 14-3-3 family of proteins bind TET2. 14-3-3s bind TET2 when phosphorylated at serine 99 (S99). AMPK-mediated phosphorylation at S99 promotes TET2 stability and increases global DNA 5-hydroxymethylcytosine. 14-3-3s’ interaction with TET2 serves to protect S99 phosphorylation. Disruption of this interaction leads to both reduced TET2 phosphorylation and decreased protein stability. Furthermore, we identify that the protein phosphatase 2A (PP2A) can interact with TET2 and dephosphorylates S99. Collectively, our study provides novel insights into the role of the N-terminal domain in TET2 regulation. Moreover, they demonstrate the dynamic nature of TET2 protein regulation that could have therapeutic implications for disease states resulting from reduced TET2 levels and/or activity.

2020-01-13 | PXD016160 | Pride

TET2 is a component of the ER complex and controls 5mC to 5hmC conversion at ER cis-regulatory regions

Project description:Estrogen receptor-alpha (ER) drives tumour development and metastasis in ER positive (ER+) breast cancer. GATA3 is a transcription factor that has been closely linked to ER function, but the role of GATA3 in ER-transcriptional activity is not clear. We sought to identify the contribution of GATA3 to the ER complex, by conducting quantitative multiplexed rapid immunoprecipitation mass spectrometry of endogenous proteins (qPLEX-RIME), to assess changes to the ER complex in response to GATA3 depletion. Unexpectedly, very few proteins were dissociated from the ER complex in the absence of GATA3, with the only major change being loss of TET2 in the ER complex. In breast cancer cells and Patient-Derived Xenograft (PDX) tissue, TET2 binding events were shown to constitute a near-total subset of ER binding events, and loss of TET2 was functionally associated with reduced activation of proliferative pathways. To investigate the TET2-ER relationship, the role of TET2 in regulating DNA modifications in ER+ breast cancer cells was examined. TET2 knockdown did not appear to result in changes to global DNA methylation, however, oxidation of methylated DNA to 5-hydroxymethylcytosine (5hmC) was significantly reduced after TET2 depletion and these events occurred at ER enhancers. These findings implicate TET2 in the production and maintenance of 5hmC at ER sites, providing a potential mechanism for TET2-mediated regulation of ER target genes.

2021-02-10 | PXD019438 | Pride

Metabolic control of innate immune activation in TET2-mutant clonal hematopoiesis

Project description:TET2 mutations drive inflammation in clonal hematopoiesis of indeterminate potential (CHIP), but the mechanism by which TET2 inactivation leads to inflammation is not understood. Here, we used in vivo genome-wide genetic perturbations in primary wildtype (WT) or Tet2 knockout (KO) Cas9+ hematopoietic stem-progenitor cells (HSPCs) in a model of zymosan peritonitis to elucidate the basis of Tet2 KO inflammation. We found that Tet2 restrains O-linked N-acetylglucosamine (O-GlcNAc) glycosyltransferase (Ogt), a Tet2 binding partner and metabolic sensor that integrates nutrient availability. Tet2 loss disrupts this Tet2-Ogt interaction, and dysregulated Ogt facilitates widespread H3K4 trimethylation including lipid-related gene loci and inflammatory lipid droplet formation. We identified ATP citrate lyase (Acly) as a critical node for lipid accumulation, inflammation, and myeloid expansion in Tet2 deficiency. In summary, we reveal that Tet2 serves as a negative regulator of the nutrient sensor Ogt, and that Tet2 inactivation leads to aberrant lipid droplet formation and inflammation.

2026-01-15 | GSE298064 | GEO

Metabolic control of innate immune activation in TET2-mutant clonal hematopoiesis [ChIP-seq]

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Tet2 and Tp53 cooperate to promote leukemia and modulate response to inflammation

Project description:Tet2 and Tp53 cooperate to promote leukemia and modulate response to inflammation

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Context Dependent Effects of Ascorbic Acid Treatment in TET2 Mutant Myeloid Neoplasia

Project description:Loss-of-function TET2 mutations (TET2MT) are common in myeloid neoplasia. TET2, a DNA dioxygenase, requires 2-oxoglutarate and Fe(II) to oxidize 5-methylcytosine. TET2MT thus result in hypermethylation and transcriptional repression. Ascorbic acid (AA) increases dioxygenase activity by facilitating Fe(III)/Fe(II) redox reaction and may alleviate some biological consequences of TET2MT by restoring dioxygenase activity. Here, we report the utility of AA in the prevention of TET2MT MN, clarify the mechanistic underpinning of the TET2-AA interactions, and demonstrate that the ability of AA to restore TET2 activity in cells depends on N- and C-terminal lysine acetylation and nature of TET2MT. Consequently, pharmacologic modulation of acetyltransferases and histone deacetylases may regulate TET dioxygenase-dependent AA effects. Thus, our study highlights the contribution of factors that may enhance or attenuate AA effects on TET2 and provides a rationale for novel therapeutic approaches including combinations of AA with class I/II HDAC inhibitor or sirtuin activators in TET2MT leukemia.

2020-09-09 | PXD020550 | Pride

Expression data from LPS/IFNgamma-treated Tet2-/- and Tet2+/+ mouse macrophages.

Project description:We examined the effect of ablation of Tet2, an epigenetic regulator of gene transcription, in the global programme of gene expression underlying pro-inflammatory activation of macrophage.

2017-01-24 | GSE81398 | GEO

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