Restoration of genome-wide 5-hydroxymethylation by azacitidine and ascorbate in TET2-deficient human pre-leukemic HSPCs
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA817283 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18361300_1.fastq.gz | Fastqsanger.gz | |||
| SRR18361300_2.fastq.gz | Fastqsanger.gz | |||
| SRR18361400_1.fastq.gz | Fastqsanger.gz | |||
| SRR18361400_2.fastq.gz | Fastqsanger.gz | |||
| SRR18361500_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 652 |
Similar Datasets
Project description:The conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) is a key step in DNA demethylation that is mediated by ten-eleven-translocation (TET) enzymes, which require ascorbate/vitamin C. Here, we report the 5hmC landscape of normal hematopoiesis and identify cell type-specific 5hmC profiles associated with active transcription and chromatin accessibility of key hematopoietic regulators. We utilized CRISPR/Cas9 to model TET2 loss-of-function mutations in primary human HSPCs. Disrupted cells exhibited increased serial replating and competitive advantage, defective erythroid/megakaryocytic differentiation, and in vivo myeloid skewing coupled with reduction of 5hmC at erythroid regulators. Azacitidine and ascorbate restored 5hmC abundance and slowed/reverted the expansion of TET2-mutant clones in vivo. These results demonstrate the key role of 5hmC in normal hematopoiesis and TET2-mutant phenotypes, and raise the possibility of utilizing these agents to treat pre-leukemia/clonal hematopoiesis and prevent leukemogenesis.
2022-05-01 | GSE198908 | GEO
Project description:Hypomethylating agents are used as frontline therapy for myelodysplastic neoplasms (MDS), but clinical response is unpredictable. To determine whether response was associated with in vivo dynamics of DNA hypomethylation, we conducted a phase 2 trial for MDS using both injection and oral azacitidine (AZA). We established that global DNA methylation levels in peripheral blood and bone marrow mononuclear cells were comparable in AZA responders and non-responders during their course of treatment. However, there were distinct baseline and early drug induced differences in CpG methylation in haematopoietic stem and progenitor cells (HSPCs) in responders compared to non-responders that overlapped with regulatory regions of genes associated with tissue patterning, cell migration and myeloid differentiation. Following six cycles of therapy when clinical response typically manifests, differential hypomethylation in responder HSPCs pointed to marrow adaptation as a driver of enhanced haematopoiesis. Taken together, CpG methylation differences in HSPCs may explain variable response to AZA.
2025-04-01 | GSE274999 | GEO
Project description:Hypomethylating agents are used as frontline therapy for myelodysplastic neoplasms (MDS), but clinical response is unpredictable. To determine whether response was associated with in vivo dynamics of DNA hypomethylation, we conducted a phase 2 trial for MDS using both injection and oral azacitidine (AZA). We established that global DNA methylation levels in peripheral blood and bone marrow mononuclear cells were comparable in AZA responders and non-responders during their course of treatment. However, there were distinct baseline and early drug induced differences in CpG methylation in haematopoietic stem and progenitor cells (HSPCs) in responders compared to non-responders that overlapped with regulatory regions of genes associated with tissue patterning, cell migration and myeloid differentiation. Following six cycles of therapy when clinical response typically manifests, differential hypomethylation in responder HSPCs pointed to marrow adaptation as a driver of enhanced haematopoiesis. Taken together, CpG methylation differences in HSPCs may explain variable response to AZA.
2025-04-01 | GSE274997 | GEO
Project description:Enhancing TET2 activity through genetic or pharmacologic approaches, such as ascorbate supplementation, can slow myeloid malignancy progression. However, ascorbate alone may be insufficient to fully activate TET2 in malignant cells due to pharmacokinetic constraints and the need for chromatin remodeling to enable effective epigenetic reprogramming. Here, we identify a novel mechanism to enhance TET2 activity via all-trans retinoic acid (ATRA), which induces RARA-mediated TET2 transcription in myeloid leukemia cells and synergizes with ascorbate to promote DNA hydroxymethylation and chromatin remodeling at key myeloid differentiation loci. Using Tet1/2/3-deficient mice and primary human AML models, we show that ATRA plus ascorbate more effectively induces differentiation, inhibits leukemia stem cell self-renewal in a TET2-dependent manner, and sensitizes AML cells to targeted therapies in vivo leading to improved survival. These findings support the combined use of ATRA and ascorbate as a strategy to enhance TET2 activity for the treatment of myeloid malignancies.
2025-09-30 | GSE298863 | GEO
Project description:Enhancing TET2 activity through genetic or pharmacologic approaches, such as ascorbate supplementation, can slow myeloid malignancy progression. However, ascorbate alone may be insufficient to fully activate TET2 in malignant cells due to pharmacokinetic constraints and the need for chromatin remodeling to enable effective epigenetic reprogramming. Here, we identify a novel mechanism to enhance TET2 activity via all-trans retinoic acid (ATRA), which induces RARA-mediated TET2 transcription in myeloid leukemia cells and synergizes with ascorbate to promote DNA hydroxymethylation and chromatin remodeling at key myeloid differentiation loci. Using Tet1/2/3-deficient mice and primary human AML models, we show that ATRA plus ascorbate more effectively induces differentiation, inhibits leukemia stem cell self-renewal in a TET2-dependent manner, and sensitizes AML cells to targeted therapies in vivo leading to improved survival. These findings support the combined use of ATRA and ascorbate as a strategy to enhance TET2 activity for the treatment of myeloid malignancies.
2025-09-30 | GSE241583 | GEO
Project description:Enhancing ten-eleven translocation 2 (TET2) activity through genetic or pharmacologic approaches, such as ascorbate supplementation, can slow myeloid malignancy progression. However, ascorbate alone may be insufficient to fully activate TET2 in malignant cells due to pharmacokinetic constraints and the need for chromatin remodeling to enable effective cellular reprogramming. Here, we identify a novel mechanism to enhance TET2 activity via all-trans retinoic acid (ATRA), which induces retinoic acid receptor alpha (RARA)-mediated TET2 transcription in myeloid leukemia cells and synergizes with ascorbate to promote DNA hydroxymethylation and chromatin remodeling at key myeloid differentiation loci. Using Tet1/2/3-deficient mice and primary human acute myeloid leukemia (AML) models, we show that ATRA plus ascorbate more effectively induces differentiation, inhibits leukemia stem cell self-renewal in a TET2-dependent manner, and sensitizes AML cells to targeted therapies in vivo, leading to improved survival. These findings support the combined use of ATRA and ascorbate as a strategy to enhance TET2 activity for the treatment of myeloid malignancies.
2025-09-30 | GSE273233 | GEO
Project description:Enhancing TET2 activity through genetic or pharmacologic approaches, such as ascorbate supplementation, can slow myeloid malignancy progression. However, ascorbate alone may be insufficient to fully activate TET2 in malignant cells due to pharmacokinetic constraints and the need for chromatin remodeling to enable effective epigenetic reprogramming. Here, we identify a novel mechanism to enhance TET2 activity via all-trans retinoic acid (ATRA), which induces RARA-mediated TET2 transcription in myeloid leukemia cells and synergizes with ascorbate to promote DNA hydroxymethylation and chromatin remodeling at key myeloid differentiation loci. Using Tet1/2/3-deficient mice and primary human AML models, we show that ATRA plus ascorbate more effectively induces differentiation, inhibits leukemia stem cell self-renewal in a TET2-dependent manner, and sensitizes AML cells to targeted therapies in vivo leading to improved survival. These findings support the combined use of ATRA and ascorbate as a strategy to enhance TET2 activity for the treatment of myeloid malignancies.
2025-09-30 | GSE298864 | GEO
Project description:Enhancing ten-eleven translocation 2 (TET2) activity through genetic or pharmacologic approaches, such as ascorbate supplementation, can slow myeloid malignancy progression. However, ascorbate alone may be insufficient to fully activate TET2 in malignant cells due to pharmacokinetic constraints and the need for chromatin remodeling to enable effective cellular reprogramming. Here, we identify a novel mechanism to enhance TET2 activity via all-trans retinoic acid (ATRA), which induces retinoic acid receptor alpha (RARA)-mediated TET2 transcription in myeloid leukemia cells and synergizes with ascorbate to promote DNA hydroxymethylation and chromatin remodeling at key myeloid differentiation loci. Using Tet1/2/3-deficient mice and primary human acute myeloid leukemia (AML) models, we show that ATRA plus ascorbate more effectively induces differentiation, inhibits leukemia stem cell self-renewal in a TET2-dependent manner, and sensitizes AML cells to targeted therapies in vivo, leading to improved survival. These findings support the combined use of ATRA and ascorbate as a strategy to enhance TET2 activity for the treatment of myeloid malignancies.
2025-09-30 | GSE298862 | GEO
Project description:Enhancing ten-eleven translocation 2 (TET2) activity through genetic or pharmacologic approaches, such as ascorbate supplementation, can slow myeloid malignancy progression. However, ascorbate alone may be insufficient to fully activate TET2 in malignant cells due to pharmacokinetic constraints and the need for chromatin remodeling to enable effective cellular reprogramming. Here, we identify a novel mechanism to enhance TET2 activity via all-trans retinoic acid (ATRA), which induces retinoic acid receptor alpha (RARA)-mediated TET2 transcription in myeloid leukemia cells and synergizes with ascorbate to promote DNA hydroxymethylation and chromatin remodeling at key myeloid differentiation loci. Using Tet1/2/3-deficient mice and primary human acute myeloid leukemia (AML) models, we show that ATRA plus ascorbate more effectively induces differentiation, inhibits leukemia stem cell self-renewal in a TET2-dependent manner, and sensitizes AML cells to targeted therapies in vivo, leading to improved survival. These findings support the combined use of ATRA and ascorbate as a strategy to enhance TET2 activity for the treatment of myeloid malignancies.
2025-09-30 | GSE298861 | GEO
Project description:Enhancing ten-eleven translocation 2 (TET2) activity through genetic or pharmacologic approaches, such as ascorbate supplementation, can slow myeloid malignancy progression. However, ascorbate alone may be insufficient to fully activate TET2 in malignant cells due to pharmacokinetic constraints and the need for chromatin remodeling to enable effective cellular reprogramming. Here, we identify a novel mechanism to enhance TET2 activity via all-trans retinoic acid (ATRA), which induces retinoic acid receptor alpha (RARA)-mediated TET2 transcription in myeloid leukemia cells and synergizes with ascorbate to promote DNA hydroxymethylation and chromatin remodeling at key myeloid differentiation loci. Using Tet1/2/3-deficient mice and primary human acute myeloid leukemia (AML) models, we show that ATRA plus ascorbate more effectively induces differentiation, inhibits leukemia stem cell self-renewal in a TET2-dependent manner, and sensitizes AML cells to targeted therapies in vivo, leading to improved survival. These findings support the combined use of ATRA and ascorbate as a strategy to enhance TET2 activity for the treatment of myeloid malignancies.
2025-09-30 | GSE241584 | GEO