Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA381698 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5417002_1.fastq.gz | Fastqsanger.gz | |||
| SRR5417002_2.fastq.gz | Fastqsanger.gz | |||
| SRR5417003_1.fastq.gz | Fastqsanger.gz | |||
| SRR5417003_2.fastq.gz | Fastqsanger.gz | |||
| SRR5417004_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 14 |
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Project description:Targeted inhibition of STAT/TET1 axis as a potent therapeutic strategy for acute myeloid leukemia
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Project description:Effective therapy of acute myeloid leukemia (AML) remains an unmet need. DNA methylcytosine dioxygenase Ten-eleven translocation 1 (TET1) is a potent oncogene in AML. Through a series of data analysis and drug screening, we identified two compounds (i.e., NSC-311068 and NSC-370284) that selectively suppress TET1 transcription and 5-hydroxymethylcytosine (5hmC) modification, and effectively inhibit cell viability in AML with high level expression of TET1 (i.e., TET1-high AML), including AML carrying t(11q23)/MLL-rearrangements and t(8;21) AML. NSC-311068 and especially NSC-370284 significantly repressed TET1-high AML progression in vivo. UC-514321, an optimized derivative of NSC-370284, exhibited an even more potent therapeutic effect and prolonged the median survival of TET1-high AML mice over three folds. NSC-370284 and its derivative showed strong synergistic effects with standard chemotherapy. NSC-370284 directly targeted STAT3/5, transcriptional activators of TET1, and thus repressed TET1 expression. Our results highlight the therapeutic potential of targeting the STAT/TET1 axis by selective inhibitors in AML treatment.
2018-01-12 | GSE97407 | GEO
Project description:Chemical Inhibition of Salt-Inducible Kinase as Therapeutic Strategy in Acute Myeloid Leukemia
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Project description:MLL-fusions are potent oncogenes that initiate aggressive forms of acute leukemia. As aberrant transcriptional regulators, MLL-fusion proteins alter gene expression in hematopoietic cells through interactions with the histone H3 lysine 79 (H3K79) methyltransferase DOT1L. Notably, interference with MLL-fusion cofactors like DOT1L is an emerging therapeutic strategy in this disease. Here we identify the histone H2B E3 ubiquitin ligase RNF20 as an additional requirement for MLL-fusion-mediated leukemogenesis. Suppressing the expression of Rnf20 in diverse models of MLL-rearranged leukemia leads to inhibition of cell proliferation; under tissue culture conditions as well as in vivo. Rnf20 knockdown leads to reduced expression of MLL-fusion target genes, including Hoxa9 and Meis1; effects that resemble Dot1l-inhibition. Using ChIP-seq, we found that H2B ubiquitination (H2Bub) is enriched in the body of MLL-fusion target genes, correlating with sites of H3K79 methylation and transcription elongation. Furthermore, we found that Rnf20 is required to maintain local levels of H3K79 di-methylation by Dot1l at Hoxa9 and Meis1. These findings support a model whereby co-transcriptional recruitment of Rnf20 at MLL-fusion target genes leads to amplification of Dot1l-mediated H3K79 methylation, thereby rendering leukemia cells dependent on Rnf20 to maintain their oncogenic transcriptional program. Examination of gene expression profiles upon RNF20 RNAi in MLL-AF9 acute myeloid leukemia cells
2013-02-19 | E-GEOD-43725 | biostudies-arrayexpress
Project description:Effective therapy of acute myeloid leukemia (AML) remains an unmet need. DNA methylcytosine dioxygenase Ten-eleven translocation 1 (TET1) is a critical oncoprotein in AML. Through a series of data analysis and drug screening, we identified two compounds (i.e., NSC-311068 and NSC-370284) that selectively suppress TET1 transcription and 5-hydroxymethylcytosine (5hmC) modification, and effectively inhibit cell viability in AML with high level expression of TET1 (i.e., TET1-high AML), including AML carrying t(11q23)/MLL-rearrangements and t(8;21) AML. NSC-311068 and especially NSC-370284 significantly repressed TET1-high AML progression in vivo. UC-514321, a structural analog of NSC-370284, exhibited a more potent therapeutic effect and prolonged the median survival of TET1-high AML mice over three folds. NSC-370284 and UC-514321 both directly target STAT3/5, transcriptional activators of TET1, and thus repress TET1 expression. They also exhibit strong synergistic effects with standard chemotherapy. Our results highlight the therapeutic potential of targeting the STAT/TET1 axis by selective inhibitors in AML treatment.
2018-01-12 | GSE101480 | 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 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
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.
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Project description:Chemical Inhibition of Salt-Inducible Kinase as Therapeutic Strategy in Acute Myeloid Leukemia [ChIP-Seq]
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