TET2 deficiency maintains leukemia stem cell self-renewal and subverts tumor immunity [model 1]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE206456 | GEO | 2023/06/23
REPOSITORIES: GEO
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Project description:To investigate the function of TET2 in the development of acute myeloid leukemia (AML), we performed gene expression profiling analysis using data obtained from RNA-seq of AML cells carrying Tet2+/+ versus Tet2-/-.
2023-06-23 | GSE206457 | GEO
Project description:To investigate the function of TET2 in the development of acute myeloid leukemia (AML), we performed gene expression profiling analysis using data obtained from RNA-seq of AML cells carrying Tet2+/+ versus Tet2-/-.
2023-06-23 | GSE206487 | GEO
Project description:To investigate the function of TET2 as an mRNA m5C demethylase in the development of acute myeloid leukemia (AML), we conducted RNA bisulfite sequencing of mRNA samples enriched from AML cells carrying Tet2+/+ versus Tet2-/- with actinomycin D treatment at different time point.
2023-06-23 | GSE231329 | 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:Loss-of-function mutations of TET2 and TP53 genes are frequently co-observed in AML patients receiving intensive chemotherapy and represent independent predictors for inferior survival in patients after stem cell transplantation. Here we show that TET2 biallelic loss or haploinsufficiency is observed in >10% AML patients with TP53 mutations and associated with poor outcome. In mice, double deletions of TET2 and P53 leads to development of T-ALL, B-ALL or AML and stimulation of pre-leukemic mice via TLR2-TRAF6-A20 axis skews leukemia development toward AML. scRNA-seq of murine blasts reveals that B cell leukemia differentiation is accompanied by transcriptional changes of ll7r and Myb while AML commitment is associated with dynamic elevation of Klf4 and Flt3. Notably, mice with AML exhibit T cell exhaustion, NK dysfunction, and MDSC-like properties which are similarly observed in AML patients with TP53/TET2 co-mutations. Lastly, we demonstrated that silencing of MEK/ERK, JAK/STAT or TLR-A20 signaling pathways, that are overexpressed in TP53/TET2-mutant AML, restores normal differentiation in vitro and in vivo. Collectively, these findings provide evidence that TP53 deficiency and TET2 loss cooperate to transform hematopoietic progenitors and play a role in AML development and identify novel targets to deliver therapy for this high-risk AML group.
2023-11-13 | GSE217867 | GEO
Project description:Studies of AML patient samples have shown that specific combinations of AML disease alleles confer an adverse outcome, however, in vivo models do not exist for the majority of common, poor-prognosis genotypes. Here we show that TET2/FLT3 mutations can cooperate to induce AML in vivo using a genetically engineered mouse model, and that this model has a defined stem-cell population with a characteristic transcriptional and epigenetic profile. TET2 and FLT3 mutations cooperate to induce site-specific changes in DNA methylation and gene expression, including at loci that regulate hematopoietic differentiation. We demonstrate that re-expression of genes that are silenced in TET2/FLT3-mutant AML restores normal differentiation, demonstrating that the epigenetic program of TET2/FLT3-mutant AML cells can be reversed in vitro and in vivo. Using ERRBS, we profiled genome-wide DNA methylation patterns of the hematopoietic stem cells (LSK) population in Wide-type, Flt3-IDT, Tet2-/-, and Tet2-/-Flt3-IDT mice, each in triplicates
2015-04-14 | E-GEOD-57114 | biostudies-arrayexpress
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:DNA methylation is tightly regulated throughout mammalian development and altered methylation patterns are a hallmark of cancer. The methylcytosine dioxygenase TET2 is frequently mutated in acute myeloid leukemia (AML) and has been suggested to protect CpG islands and promoters from aberrant methylation. By generating a novel mouse model of Tet2-deficient AML we show that loss of Tet2 in hematopoietic cells leads to progressive hypermethylation of active enhancer elements and altered expression of genes implicated in tumorigenesis. In contrast, CpG island and promoter methylation does not change in a Tet2-dependent manner. Furthermore, we confirm this specific enhancer hypermethylation phenotype in human AML patients. Thus, we propose that TET2 prevents leukemic transformation of hematopoietic cells by protecting enhancers from aberrant DNA methylation. Gene expression profiles from Tet2-/-;AML1-ETO and Tet2fl/fl;AML1-ETO in vitro-grown hematopoietic cells were compared using GeneChip Mouse Gene ST 2.0 Arrays (Affymetrix). Expression changes were investigated at early (passage 2) and late (passage 10) timepoints after Tet2 disruption.
2015-04-22 | E-GEOD-59586 | biostudies-arrayexpress