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Homo sapiens

ABSTRACT: Targeted inhibition of STAT/TET1 axis as a potent therapeutic strategy for acute myeloid leukemia

PROVIDER: PRJNA394528 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR5829212.fastq.gz	Fastqsanger.gz
	SRR5829213.fastq.gz	Fastqsanger.gz
	SRR5829214.fastq.gz	Fastqsanger.gz
	SRR5829215.fastq.gz	Fastqsanger.gz
	SRR5829216.fastq.gz	Fastqsanger.gz

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Homo sapiens

Project description:Targeted inhibition of TET1 transcription as a potent therapeutic strategy for acute myeloid leukemia

| PRJNA381698 | ENA

Targeted inhibition of TET1 transcription as a potent therapeutic strategy for acute myeloid leukemia

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

Targeted inhibition of STAT/TET1 axis as a potent therapeutic strategy for acute myeloid leukemia

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

Chemical Inhibition of Salt-Inducible Kinase as Therapeutic Strategy in Acute Myeloid Leukemia

Project description:Chemical Inhibition of Salt-Inducible Kinase as Therapeutic Strategy in Acute Myeloid Leukemia

| PRJNA533070 | ENA

Expression profiling of primary leukemia initiating cell-enriched population induced by AML1-ETO9a

Project description:Combined gene expression and DNA occupancy profiling identifies JAK/STAT signaling as a valid therapeutic target of t(8;21) AML t(8;21) is commonly associated with acute myeloid leukemia (AML). The resulting AML1-ETO fusion proteins are involved in the pathogenesis of AML. To identify novel molecular and therapeutic targets, we performed combined gene expression and promoter occupancy profiling using a primary leukemia initiating cell-enriched population induced by AML1-ETO9a (AE9a). CD45, a negative regulator of cytokine/growth factor receptor and JAK/STAT signaling, is greatly downregulated; furthermore JAK1 and JAK2 are upregulated in these leukemia cells. Consequently, JAK/STAT signaling is enhanced in the AE9a leukemia cells. Importantly, AE9a leukemia cells are highly susceptible to perturbation of JAK/STAT signaling, and a JAK2-selective inhibitor, TG101209, effectively targets these leukemia cells in vivo, suggesting the potential efficacy of JAK2 inhibitors in treating t(8;21) AML. Wild-type or AE9a leukemic samples in triplicate.

2012-09-04 | E-GEOD-15195 | biostudies-arrayexpress

A Selective Small-Molecule STAT5 PROTAC Degrader Capable of Achieving Tumor Regression In Vivo

Project description:The signal transducer and activator of transcription 5 (STAT5) is an attractive therapeutic target but successful targeting of STAT5 has proved to be difficult. We report herein the development of AK-2292 as a first, potent and selective small-molecule degrader of both STAT5A and STAT5B isoforms. AK-2292 induces degradation of STAT5A/B proteins with an outstanding selectivity over all other STAT proteins and >6,000 non-STAT proteins, leading to selective inhibition of STAT5 activity in cells. AK-2292 effectively induces STAT5 depletion in normal mouse tissues and human chronic myeloid leukemia (CML) xenograft tissues and achieves tumor regression in two CML xenograft mouse models at well-tolerated dose-schedules. AK-2292 is not only a powerful research tool with which to investigate the biology of STAT5 and therapeutic potential of selective STAT5 protein depletion and inhibition in vitro and in vivo, but also a promising lead compound toward ultimate development of a STAT5-targeted therapy.

2023-01-25 | PXD037895 | Pride

Combined Inhibition of JAK/STAT Pathway and Lysine Demethylase 1 as a Novel Therapeutic Strategy in CSF3R/CEBPA Mutant Acute Myeloid Leukemia

Project description:Combined Inhibition of JAK/STAT Pathway and Lysine Demethylase 1 as a Novel Therapeutic Strategy in CSF3R/CEBPA Mutant Acute Myeloid Leukemia

| PRJNA575722 | ENA

Chemical Inhibition of Salt-Inducible Kinase as Therapeutic Strategy in Acute Myeloid Leukemia [RNA-Seq]

Project description:Chemical Inhibition of Salt-Inducible Kinase as Therapeutic Strategy in Acute Myeloid Leukemia [RNA-Seq]

| PRJNA533192 | ENA

Chemical Inhibition of Salt-Inducible Kinase as Therapeutic Strategy in Acute Myeloid Leukemia [ChIP-Seq]

Project description:Chemical Inhibition of Salt-Inducible Kinase as Therapeutic Strategy in Acute Myeloid Leukemia [ChIP-Seq]

| PRJNA533061 | ENA

Ferritinophagy is a Druggable Vulnerability of Quiescent Leukemic Stem Cells in Acute Myeloid Leukemia

Project description:Acute myeloid leukemia (AML) remains a challenging hematological malignancy with poor prognosis and limited treatment options. Post-therapy relapse, particularly driven by leukemic stem cells (LSCs), contributes to therapeutic failure and adverse outcome. Here, we investigated the role of quiescence and its associated molecular mechanisms in AML pathogenesis and identified potential vulnerabilities for therapeutic intervention. We found that quiescent AML cells, enriched for LSC functions, exhibited a distinct gene set that served as a significant prognostic factor for poor outcomes in AML patients. Furthermore, quiescent cells displayed heightened autophagic activity, with a reliance on ferritinophagy, a selective form of autophagy mediated by Nuclear Receptor Coactivator 4 (NCOA4), for iron bioavailability. Inhibition of NCOA4 genetically or chemically showed potent anti-leukemic effects, particularly targeting the LSC compartment. These findings uncover that ferritinophagy inhibition may represent a promising therapeutic strategy for patients with AML.

2024-06-13 | PXD042796 | Pride

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