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Genetic and pharmacological restoration of TET2 function blocks stem cell self-renewal and progression of leukemia

ABSTRACT: Genetic and pharmacological restoration of TET2 function blocks stem cell self-renewal and progression of leukemia

OTHER RELATED OMICS DATASETS IN: GSE97442GSE97440GSE100041

PROVIDER: PRJNA381784 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR5419840.fastq.gz	Fastqsanger.gz
	SRR5419850.fastq.gz	Fastqsanger.gz
	SRR5419860.fastq.gz	Fastqsanger.gz
	SRR5419870.fastq.gz	Fastqsanger.gz
	SRR5419841.fastq.gz	Fastqsanger.gz

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Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression.

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 α-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.

| S-EPMC5755977 | biostudies-literature

Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation

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

Genetic and pharmacological restoration of TET2 function blocks stem cell self-renewal and progression of leukemia

Project description:This SuperSeries is composed of the SubSeries listed below.

2017-08-21 | GSE97442 | GEO

Pharmacological Activation of STING blocks SARS-CoV-2 infection

Project description:Pharmacological Activation of STING blocks SARS-CoV-2 infection

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Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation

2011-07-01 | GSE27816 | GEO

Transcriptional and epigenetic reprogramming mediated by chronic IL1β exposure drives self-renewal ability and myeloid priming in TET2 deficient stem and progenitor cells [10x_scRNAseq]

Project description:Clonal hematopoiesis (CH) increases risk for the development of hematological malignancy and cardiovascular disease. IL1β is elevated in patients with CH and its inhibition mitigates cardiovascular risk in murine models with Tet2 loss-of-function. How IL1β alters population dynamics of hematopoietic cells upon Tet2 deletion (Tet2-KO) is not well understood. We demonstrated IL1β expands Tet2-KO neutrophils, monocytes/macrophages, and long-term hematopoietic stem cells with reduced lymphopoiesis. IL1β promotes myeloid bias over other lineages coinciding with failure to demethylate lineage associated enhancer and transcription factor binding sites in Tet2-KO HSPCs. IL1β enhanced self-renewal ability of Tet2-KO HSPCs by upregulating genes associated with self-renewal potential and by failure to demethylate binding sites of transcription factors promoting differentiation. IL1β-mediated premalignant phenotype is reversed by IL1β antagonist anakinra or deletion of the Il1 receptor, in vivo. Our results demonstrated that targeting IL-1 signaling could be an efficient early intervention strategy in preleukemic disorders.

2023-10-27 | GSE209994 | GEO

Transcriptional and epigenetic reprogramming mediated by chronic IL1β exposure drives self-renewal ability and myeloid priming in TET2 deficient stem and progenitor cells [Bisulfite-Seq]

2023-10-27 | GSE210025 | GEO

Chromatin-associated LTR RNA m5C oxidation by TET2 regulates chromatin state and leukemogenesis [seq_RNA-caRNA]

Project description:Mutation of Ten-eleven translocation enzyme 2 (TET2) drives myeloid malignancy initiation and progression. TET2 deficiency is known to cause a globally opened chromatin state and activation of genes contributing to aberrant hematopoietic stem cell self-renewal. However, the open chromatin observed in TET2-deficient mouse embryonic stem cells, leukemic cells and hematopoietic progenitor and stem cells is inconsistent with the designated role of DNA 5mC oxidation of TET2. We show here that chromatin-associated retrotransposon RNA 5-methylcytosine (m5C) can be recognized by the methyl-CpG-binding domain protein MBD6, which guides deubiquitination of nearby histone H2AK119ub to promote an open chromatin state. TET2 oxidizes m5C and antagonizes this MBD6-dependent H2AK119ub deubiquitination. Thereby, TET2 depletion leads to globally decreased H2AK119ub, more open chromatin, and increased transcription in stem cells. TET2 mutant human leukemia becomes dependent on this gene activation pathway, with MBD6 depletion selectively blocks proliferation of TET2 mutant leukemic cells and fully reverses the hematopoiesis defects caused by Tet2 loss, both in vitro and in vivo. Altogether, our findings reveal a chromatin regulation pathway by TET2 through retrotransposon RNA m5C oxidation and identify the downstream MBD6 protein as a feasible target for developing therapies specific against TET2 mutant malignancies.

2024-07-25 | GSE269961 | GEO

Chromatin-associated LTR RNA m5C oxidation by TET2 regulates chromatin state and leukemogenesis [seq_DNA-MeDIP]

2024-07-25 | GSE269960 | GEO

Chromatin-associated LTR RNA m5C oxidation by TET2 regulates chromatin state and leukemogenesis [seq_DNA-CUTandTag]

2024-07-25 | GSE269959 | GEO