Genetic and pharmacological restoration of TET2 function blocks stem cell self-renewal and progression of leukemia
Ontology highlight
ABSTRACT:
OTHER RELATED OMICS DATASETS IN: PRJNA381792PRJNA390544PRJNA390176PRJNA381784
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE97442 | GEO | 2017/08/21
SECONDARY ACCESSION(S): PRJNA381784
REPOSITORIES: GEO
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Project description:Loss-of-function mutations in TET2 occur frequently in patients with clonal hematopoiesis, myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML) and are associated with a DNA hypermethylation phenotype. To determine the role of TET2 deficiency in leukemia stem cell maintenance, we generated a reversible transgenic RNAi mouse to model restoration of endogenous Tet2 expression. Tet2 restoration reverses aberrant hematopoietic stem and progenitor cell (HSPC) self-renewal in vitro and in vivo. Treatment with vitamin C, a co-factor of Fe2+ and ?-KG-dependent dioxygenases, mimics TET2 restoration by enhancing 5-hydroxymethylcytosine formation in Tet2-deficient mouse HSPCs and suppresses human leukemic colony formation and leukemia progression of primary human leukemia PDXs. Vitamin C also drives DNA hypomethylation and expression of a TET2-dependent gene signature in human leukemia cell lines. Furthermore, TET-mediated DNA oxidation induced by vitamin C treatment in leukemia cells enhances their sensitivity to PARP inhibition and could provide a safe and effective combination strategy to selectively target TET deficiency in cancer. PAPERCLIP.
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Project description:Genetic and pharmacological restoration of TET2 function blocks stem cell self-renewal and progression of leukemia
| PRJNA381784 | ENA
Project description:Purpose: The goal of this study was to compare the transcriptome of FACS-purified bone marrow BL/6 (WT) or CD93-/- (KO) LSKs and BL/6 (WT) or CD93-/- (KO) LSCs. We also compared the transcriptome of FACS-purified bone marrow LSCs isolated from BL/6 mice previously treated with MCP or Veh in vivo. Methods: Transcriptomic analysis of CD93-proficient and deficient bone marrow LSKs and CML LSCs or CML LSCs upon treatment with MCP or Veh, were assessed in biological replicates using Illumina. qRT–PCR validation was performed using SYBR Green assays. Results: We mapped around 30 million sequence reads per sample to the mouse genome (GRCm38 - mm10) and identified expressed transcripts in studied samples. RNA-seq data confirmed stable expression of known housekeeping genes. Differentially expressed genes among conditions were identified with a fold change ≥1.5 and FDR p-value <0.05. Conclusions: Our study represents the first detailed transcriptome analysis of CD93-proficient and deficient bone marrow LSKs and LSCs isolated from BM of naïve and CML mice generated by RNA-seq. technology. Our results show that CD93-signaling triggers stem cell maintenance- and cell proliferation-promoting signaling pathways in CML LSCs. In addition, we showed transcriptome analysis of FACS-purified bone marrow LSCs isolated from BL/6 (WT) mice which were previously treated with MCP or Veh in vivo. Our results show that MCP treatment suppresses the stem cell maintenance- and cell proliferation-promoting signaling pathways in CML LSCs.
2021-02-07 | GSE149358 | GEO
Project description:Somatic loss-of-function mutations in the ten-eleven translocation 2 (TET2) gene occur in a significant proportion of patients with myeloid malignancies. Although there are extensive genetic data implicating TET2 mutations in myeloid transformation, the consequences of Tet2 loss in hematopoietic development have not been delineated. We report here an animal model of conditional Tet2 loss in the hematopoietic compartment that leads to increased stem cell self-renewal in vivo as assessed by competitive transplant assays. Tet2 loss leads to a progressive enlargement of the hematopoietic stem cell compartment and eventual myeloproliferation in vivo, including splenomegaly, monocytosis, and extramedullary hematopoiesis. In addition, Tet2(+/-) mice also displayed increased stem cell self-renewal and extramedullary hematopoiesis, suggesting that Tet2 haploinsufficiency contributes to hematopoietic transformation in vivo.
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Project description:BackgroundVitamin C suppresses leukaemogenesis by modulating Tet methylcytosine dioxygenase (TET) activity. However, its beneficial effect in the treatment of patients with acute myeloid leukaemia (AML) remains controversial. In this study, we aimed to identify a potential predictive biomarker for vitamin C treatment in AML.MethodsGene expression patterns and their relevance to the survival of AML patients were analysed with The Cancer Genome Atlas (TCGA) and Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database cases. In vitro experiments were performed on AML cell lines, a SLC2A3-knockdown cell line and patient-derived primary AML cells.ResultsSLC2A3 expression was significantly decreased in leukaemic blast cells. Below-median SLC2A3 expression was associated with poor overall survival. Low SLC2A3 expression was associated with less effective demethylation, and a diminished vitamin C effect in the AML and lymphoma cell lines. SLC2A3 knockdown in the KG-1 cell line decreased the response of vitamin C. In patient-derived primary AML cells, vitamin C only restored TET2 activity when SLC2A3 was expressed.ConclusionSLC2A3 could be used as a potential biomarker to predict the effect of vitamin C treatment in AML.
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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-/-.
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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-/-.
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Project description:Mutant RAS oncoproteins activate signaling molecules that drive oncogenesis in multiple human tumors including acute myelogenous leukemia (AML). However, the specific function of these pathways in AML is unclear. To elucidate the downstream functions of activated NRAS in AML, we employed a murine model of AML harboring Mll-AF9 and NRASG12V. We found that NRASG12V enforced leukemia self-renewal gene expression signatures and was required to maintain an MLL-AF9 and MYB-dependent gene expression program. In a multiplexed analysis of RAS-dependent signaling intermediates, the leukemia stem cell compartment was preferentially sensitive to RAS withdrawal. Use of RAS-pathway inhibitors showed that NRASG12V maintained leukemia self-renewal through mTOR and MEK pathway activation, implicating these pathways as potential targets for cancer stem cell-specific therapies. Mice harboring NRASG12V/Mll-AF9 AML were treated with doxycyline to abolish NRASG12V expression. Leukemia samples were harvested at 12 hour intervals after doxycyline treatment. RNA was extracted from these samples and submitted for gene expression microarray analysis
2014-11-16 | E-GEOD-49038 | biostudies-arrayexpress
Project description:Hyperactivation of the mTOR pathway impairs hematopoietic stem cell (HSC) functions and promotes leukemogenesis. mTORC1 and mTORC2 differentially control normal and leukemic stem cell functions. mTORC1 regulates p70 ribosomal protein S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E-binding (eIF4E-binding) protein 1 (4E-BP1), and mTORC2 modulates AKT activation. Given the extensive crosstalk that occurs between mTORC1 and mTORC2 signaling pathways, we assessed the role of the mTORC1 substrate S6K1 in the regulation of both normal HSC functions and in leukemogenesis driven by the mixed lineage leukemia (MLL) fusion oncogene MLL-AF9. We demonstrated that S6K1 deficiency impairs self-renewal of murine HSCs by reducing p21 expression. Loss of S6K1 also improved survival in mice transplanted with MLL-AF9-positive leukemic stem cells by modulating AKT and 4E-BP1 phosphorylation. Taken together, these results suggest that S6K1 acts through multiple targets of the mTOR pathway to promote self-renewal and leukemia progression. Given the recent interest in S6K1 as a potential therapeutic target in cancer, our results further support targeting this molecule as a potential strategy for treatment of myeloid malignancies.
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Project description:Mutant RAS oncoproteins activate signaling molecules that drive oncogenesis in multiple human tumors including acute myelogenous leukemia (AML). However, the specific function of these pathways in AML is unclear. To elucidate the downstream functions of activated NRAS in AML, we employed a murine model of AML harboring Mll-AF9 and NRASG12V. We found that NRASG12V enforced leukemia self-renewal gene expression signatures and was required to maintain an MLL-AF9 and MYB-dependent gene expression program. In a multiplexed analysis of RAS-dependent signaling intermediates, the leukemia stem cell compartment was preferentially sensitive to RAS withdrawal. Use of RAS-pathway inhibitors showed that NRASG12V maintained leukemia self-renewal through mTOR and MEK pathway activation, implicating these pathways as potential targets for cancer stem cell-specific therapies.
2014-11-16 | GSE49038 | GEO