PI3K signaling is essential for leukemic transformation of Tet2 mutated pre-leukemic hematopoietic stem cells
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE240024 | GEO | 2026/04/01
REPOSITORIES: GEO
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Project description:Inhibition of PI3K rescues Dnmt3a loss driven leukemia. The signaling pathways by which DNMT3A mutations contribute to myeloid transformation are poorly understood. We investigated that loss of Dnmt3a in HSC/Ps results in myeloproliferation, which is associated with hyperactivation of the PI3Kinase pathway.
2022-11-30 | GSE208437 | GEO
Project description:To investigate the role of PI3K in Dnmt3a loss driven leukemia, bone marrow cells from wildtype or Dnmt3a knockout mice were assayed for differential gene expression.The signaling pathways by which DNMT3A mutations contribute to myeloid transformation are poorly understood. We investigated that loss of Dnmt3a in HSC/Ps results in myeloproliferation, which is associated with hyperactivation of the PI3Kinase pathway.
2022-11-30 | GSE208435 | GEO
Project description:Recurrent somatic mutations in TET2 and in other genes that regulate the epigenetic state have been identified in patients with myeloid malignancies and in other cancers. However, the in vivo effects of Tet2 loss have not been delineated. We report here that Tet2 loss leads to increased stem-cell self-renewal and to progressive stem cell expansion. Consistent with human mutational data, Tet2 loss leads to myeloproliferation in vivo, notable for splenomegaly and monocytic proliferation. In addition, haploinsufficiency for Tet2 confers increased self-renewal and myeloproliferation, suggesting that the monoallelic TET2 mutations found in most TET2-mutant leukemia patients contribute to myeloid transformation. This work demonstrates that absent or reduced Tet2 function leads to enhanced stem cell function in vivo and to myeloid transformation. These studies show that a ubiquitin ligase-substrate pair can orchestrate the molecular program of HSC differentitiation Gene expression profiles from WT and Tet2-/- sorted LSK and myeloid progenitors (CMP and GMP) were compared using genome wide mRNA expression profiling by Affymetrix genechip arrays (Mouse 430 2.0) and key targets were validated by chromatin immunoprecipitation experiments.
2011-07-01 | E-GEOD-27816 | biostudies-arrayexpress
Project description:Recurrent somatic mutations in TET2 and in other genes that regulate the epigenetic state have been identified in patients with myeloid malignancies and in other cancers. However, the in vivo effects of Tet2 loss have not been delineated. We report here that Tet2 loss leads to increased stem-cell self-renewal and to progressive stem cell expansion. Consistent with human mutational data, Tet2 loss leads to myeloproliferation in vivo, notable for splenomegaly and monocytic proliferation. In addition, haploinsufficiency for Tet2 confers increased self-renewal and myeloproliferation, suggesting that the monoallelic TET2 mutations found in most TET2-mutant leukemia patients contribute to myeloid transformation. This work demonstrates that absent or reduced Tet2 function leads to enhanced stem cell function in vivo and to myeloid transformation. These studies show that a ubiquitin ligase-substrate pair can orchestrate the molecular program of HSC differentitiation
2011-07-01 | GSE27816 | GEO
Project description:Ten-Eleven-translocation (Tet2) encodes an epigenetic modifier enzyme and is mutated somatically during age-associated clonal hematopoiesis of indeterminate potential (CHIP) as well as in myeloid malignancies 1-7. Tet2 deficiency leads to increased hematopoietic stem cell (HSC) renewal in human 7 and mouse 8. However, the development of myeloproliferation and myeloid malignancies occurs at late age, and only occasionally in humans 2,6,7,9 and in 50-75% of Tet2 deficient animals 8,10,11, suggesting that undefined triggers are required for pre-leukemic myeloid expansion. Our studies reveal that Tet2 deficient mice can exhibit high levels of plasma IL-6, systemic dissemination of indigenous gut bacteria and increased intestinal permeability that correlate with the development of a pre-leukemic myeloproliferative phenotype. Increased intestinal permeability was linked to a large number of transcriptional changes in the jejunum, especially among genes involved in defense response to bacterium and intestinal barrier function. Strikingly, antibiotic treatment reduced plasma IL-6 levels and both, prevented early myeloid expansion and reversed the pre-leukemic myeloproliferative phenotype in Tet2-/- mice. In summary, we show that Tet2 deficiency promotes intestinal bacterial translocation and subsequent systemic inflammation, and that gut-derived microbial signals are required for the development of pre-leukemic myeloproliferation in a Tet2-deficient host. Our studies suggest that controlling bacterial translocation and bacteria-associated systemic inflammation could decrease the risk of myeloid malignancies significantly in individuals with somatic Tet2 mutations.
2018-03-15 | GSE99333 | GEO
Project description:Hematopoietic stem cells (HSCs) manifest impaired recovery and self-renewal with a concomitant increase in progenitor content (HPCs) when exposed to ambient air as opposed to physioxia. Mechanisms behind this distinction are poorly understood but have the potential to enhance HSC function for bone marrow transplantation. High resolution transcriptomic analysis revealed that HSCs under physioxia (HSCs- P) upregulate genes involved in self-renewal and quiescence but downregulate genes involved in apoptosis and differentiation compared to HSCs-A. Remarkably, among several genes, Tet2 was significantly downregulated in HSC-Ps compared to HSC-As, which was associated with reduced 5-hydroxymethylcytosine (5-hmC) levels in HSC-Ps. Interestingly, individuals carrying the TET2 mutation in their HSCs are at a higher risk of developing clonal hematopoiesis, myeloid leukemias and cardiovascular disease. Loss of Tet2 in mice results in more HSCs and enhanced self-renewal. TET enzymes are α-ketoglutarate, iron and oxygen-dependent dioxygenases that convert 5-methylcytosine to 5-hydroxymethylcytosine thereby promoting active transcription. We evaluated whether physioxia affects the numbers and function of HSCs and HPCs from Tet2-/- mice similar to wildtype (WT) mice. In contrast to WT-HSCs, we observed complete non-responsiveness of Tet2-/- HSCs to changes in oxygen tension. Tet2-/- HSCs and HPCs exhibited similar numbers and function under physioxia and ambient air. The lack of functional responsiveness to changes in oxygen tension in Tet2-/- HSCs was associated with similar changes in genes involved in self-renewal and quiescence among WT-HSC-Ps, Tet2-/- HSC-Ps and Tet2-/- HSC-As. Our findings define a novel molecular program involving Tet2 in regulating the self-renewal of HSCs under physioxia.
2022-01-07 | GSE192992 | GEO
Project description:Hematopoietic stem cells (HSCs) manifest impaired recovery and self-renewal with a concomitant increase in progenitor content (HPCs) when exposed to ambient air as opposed to physioxia. Mechanisms behind this distinction are poorly understood but have the potential to enhance HSC function for bone marrow transplantation. High resolution transcriptomic analysis revealed that HSCs under physioxia (HSCs- P) upregulate genes involved in self-renewal and quiescence but downregulate genes involved in apoptosis and differentiation compared to HSCs-A. Remarkably, among several genes, Tet2 was significantly downregulated in HSC-Ps compared to HSC-As, which was associated with reduced 5-hydroxymethylcytosine (5-hmC) levels in HSC-Ps. Interestingly, individuals carrying the TET2 mutation in their HSCs are at a higher risk of developing clonal hematopoiesis, myeloid leukemias and cardiovascular disease. Loss of Tet2 in mice results in more HSCs and enhanced self-renewal. TET enzymes are α-ketoglutarate, iron and oxygen-dependent dioxygenases that convert 5-methylcytosine to 5-hydroxymethylcytosine thereby promoting active transcription. We evaluated whether physioxia affects the numbers and function of HSCs and HPCs from Tet2-/- mice similar to wildtype (WT) mice. In contrast to WT-HSCs, we observed complete non-responsiveness of Tet2-/- HSCs to changes in oxygen tension. Tet2-/- HSCs and HPCs exhibited similar numbers and function under physioxia and ambient air. The lack of functional responsiveness to changes in oxygen tension in Tet2-/- HSCs was associated with similar changes in genes involved in self-renewal and quiescence among WT-HSC-Ps, Tet2-/- HSC-Ps and Tet2-/- HSC-As. Our findings define a novel molecular program involving Tet2 in regulating the self-renewal of HSCs under physioxia.
2022-01-07 | GSE192988 | GEO
Project description:Cancer-associated IDH mutations are characterized by neomorphic enzyme activity and resultant 2 hydroxyglutarate (2HG) production. Mutational and epigenetic profiling of a large AML patient cohort revealed that IDH1/2-mutant AMLs display global DNA hypermethylation and a specific hypermethylation signature. Furthermore, expression of 2HG-producing IDH alleles in cells rapidly induced global DNA hypermethylation. In the AML cohort, IDH1/2 mutations were mutually exclusive with mutations in the α-ketoglutarate-dependent enzyme TET2, and TET2 loss-of function mutations associated with similar epigenetic defects as IDH1/2 mutants. Consistent with these genetic and epigenetic data, expression of IDH mutants impaired TET2 catalytic function in cells. Finally, either expression of mutant IDH1/2 or Tet2 depletion impaired hematopoietic differentiation and increased stem cell marker expression, suggesting a shared pro-leukemogenic effect. DNA methylation and gene expression profiling in IDH1/2 mutant vs. IDH1/2 wild-type AML
2010-12-03 | E-GEOD-24505 | biostudies-arrayexpress
Project description:Despite rapid advances in mapping genetic drivers and gene expression changes in hematopoietic stem cells (HSCs), there is a relative paucity of studies at the protein level. Here, we perform a deep, multi-omic characterization (epigenome, transcriptome and proteome) of HSCs carrying a loss-of-function mutation in Tet2, a key driver of increased self-renewal in blood cancers. Using state-of-the-art, multiplexed, low-input mass spectrometry (MS)-based proteomics, we profile wildtype (WT) and TET2-deficient (Tet2-/-) HSCs and show that the proteome captures previously unrecognized molecular processes which define the pre-leukemic HSC molecular landscape. Specifically, we obtain more accurate stratification of WT and Tet2-/- HSCs than transcriptomic approaches and identify extracellular matrix (ECM) molecules as novel points of dysregulation upon TET2 loss. HSC expansion assays using ECM-functionalized hydrogels confirm a selective effect on the expansion of Tet2-mutant HSCs. Taken together, our study represents a comprehensive molecular characterization of Tet2-mutant HSCs and identifies a previously unanticipated role of ECM molecules in regulating self-renewal of disease-driving HSCs.
2025-11-13 | PXD059814 | Pride
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