Tp53 and Tet2 mutations cooperatively transform GMP (RNA-Seq)
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1203221 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31835733.fastq.gz | Fastqsanger.gz | |||
| SRR31835734.fastq.gz | Fastqsanger.gz | |||
| SRR31835735.fastq.gz | Fastqsanger.gz | |||
| SRR31835736.fastq.gz | Fastqsanger.gz | |||
| SRR31835737.fastq.gz | Fastqsanger.gz |
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Project description:Mutations and deletions in TP53 are associated with adverse outcome in patients with myeloid malignancies and developing improved therapies for TP53-mutant leukemias is of urgent need. Here we identify mutations in TET2 as the most commonly co-existing mutation in TP53 mutant acute myeloid leukemia (AML) patients. Combined hematopoietic-specific deletion of TET2 and TP53 in mice enhanced self-renewal compared to deletion of either gene alone. Tet2/Tp53 double knockout mice developed serially transplantable AML. Both mice as well as patients with AML and combined TET2/TP53 alterations upregulated innate immune signaling in malignant cells. Mice with TET2/TP53 loss had expansion of monocytic myeloid-derived suppressor cells which impaired T cell proliferation. Moreover, patients and mice with TP53/TET2 double mutant AML upregulated TIGIT ligands CD155 on malignant cells. TIGIT blocking antibodies augmented the ability of NK cells to kill Tet2/Tp53 double mutant AML cells, reduced leukemic burden, and extended the survival of TET2/TP53 double knockout mice. These data thereby identify a previously unexplored link between TET2 and TP53 mutations and highlight therapeutic means to overcome the immunosuppressive bone marrow environment in this adverse subtype of AML.
2025-05-12 | GSE285355 | GEO
Project description:Tp53 and Tet2 mutations cooperatively transform progenitors (RNA-Seq)
| PRJNA1172353 | ENA
Project description:Mutations and deletions in TP53 are associated with adverse outcome in patients with myeloid malignancies and developing improved therapies for TP53-mutant leukemias is of urgent need. Here we identify mutations in TET2 as the most commonly co-existing mutation in TP53 mutant acute myeloid leukemia (AML) patients. Combined hematopoietic-specific deletion of TET2 and TP53 in mice enhanced self-renewal compared to deletion of either gene alone. Tet2/Tp53 double knockout mice developed serially transplantable AML. Both mice as well as patients with AML and combined TET2/TP53 alterations upregulated innate immune signaling in malignant cells. Mice with TET2/TP53 loss had expansion of monocytic myeloid-derived suppressor cells which impaired T cell proliferation. Moreover, patients and mice with TP53/TET2 double mutant AML upregulated TIGIT ligands CD155 and CD112 on malignant cells. TIGIT blocking antibodies augmented the ability of NK cells to kill Tet2/Tp53 double mutant AML cells, reduced leukemic burden, and extended the survival of TET2/TP53 double knockout mice. These data thereby identify a previously unexplored link between TET2 and TP53 mutations and highlight therapeutic means to overcome the immunosuppressive bone marrow environment in this adverse subtype of AML.
2025-05-12 | GSE279386 | 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: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
Project description:The study was a comparison of gene expression using RNA-seq. We analyzed the stem and progenitor cells from WT and Vav-cre+ Tet2fl/fl Flt3-ITD (T2F3) mice. We isolated stem cells LSK (lin- sca+ kit+) and granulocyte-macrophage progenitors GMP (lin- sca- kit+ fcgr+ cd34+) cells from bone marrow. Comparisons were made across genotypes WT vs. T2F3 and cell types LSK vs. GMP. Comparison of WT and Tet2-/-Flt3ITD bone marrow stem and progenitor cells.
2015-05-01 | E-GEOD-57244 | 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 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:Tet2 and Tp53 cooperate to promote leukemia and modulate response to inflammation
| PRJNA1305003 | ENA
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
Project description:TP53 is the most commonly mutated gene in human cancer, typically occurring in association with complex cytogenetics and dismal outcomes. Understanding the genetic and non-genetic determinants of TP53- mutation driven clonal evolution and subsequent transformation is a crucial step towards the design of rational therapeutic strategies. Here, we carry out allelic resolution single-cell multi-omic analysis of haematopoietic stem/progenitor cells (HSPC) from patients with a myeloproliferative neoplasm who transform to TP53- mutant secondary acute myeloid leukaemia (AML), a tractable model of TP53 -mutant cancer evolution.
2023-05-10 | GSE226340 | GEO