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Homo sapiens

ABSTRACT: Mapping STAT1 pS727 occupancy and effect of cortistatin A (CA) on STAT1 occupancy in JAK2-driven neoplasms

PROVIDER: PRJNA392122 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR5761810.fastq.gz	Fastqsanger.gz
	SRR5761820.fastq.gz	Fastqsanger.gz
	SRR5761811.fastq.gz	Fastqsanger.gz
	SRR5761812.fastq.gz	Fastqsanger.gz
	SRR5761813.fastq.gz	Fastqsanger.gz

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Homo sapiens

Project description:Effect of cortistatin A (CA) on enhancer occupancy in CA-sensitive and -insensitive human cell lines

| PRJNA273301 | ENA

Mapping STAT1 pS727 occupancy and effect of cortistatin A (CA) on STAT1 occupancy in JAK2-driven neoplasms

Project description:We characterized the marine natural product cortistatin A (CA) as an inhibitor of CDK8 to determine whether pharmacologic inhibition of CDK8 regulates super-enhancer function and inhibits AML proliferation. In this series, we use ChIP-seq of STAT1 and STAT1 pS727 to examine how the localization of STAT1 is affected by inhibition of serine 727 phosphorylation

2018-04-11 | GSE100566 | GEO

Development of resistance to type II JAK2 inhibition in MPN depends on AXL kinase and is targetable

Project description:Purpose: Myeloproliferative neoplasms (MPN) dysregulate JAK2 signaling. Since clinical JAK2 inhibitors have limited disease-modifying effects, type II JAK2 inhibitors such as CHZ868 stabilizing inactive JAK2 and reducing MPN clones, gain interest. We studied whether MPN cells escape from type ll inhibition.Methods: MPN cells were continuously exposed to CHZ868. We used phosphoproteomic analyses and ATAC-/RNA-sequencing to characterize acquired resistance to type II JAK2 inhibition, and targeted candidate mediators in MPN cells and mice.Results: MPN cells showed increased IC50 and reduced apoptosis upon CHZ868 reflecting acquired resistance to JAK2 inhibition. Among >2500 differential phospho-sites, MAPK pathway activation was most prominent, while JAK2-STAT3/5 remained suppressed. Altered histone occupancy promoting AP-1/GATA binding motif exposure associated with upregulated AXL kinase and enriched RAS target gene profiles. AXL knockdown resensitized MPN cells and combined JAK2/AXL inhibition using bemcentinib or gilteritinib reduced IC50 to levels of sensitive cells. While resistant cells induced tumor growth in NSG mice despite JAK2 inhibition, JAK2/AXL inhibition largely prevented tumor progression. Since inhibitors of MAPK pathway kinases such as MEK are clinically used in other malignancies, we evaluated JAK2/MAPK inhibition with trametinib to interfere with AXL-MAPK-induced resistance. Tumor growth was halted similarly to JAK2/AXL inhibition and in a systemic cell line-derived mouse model, marrow infiltration was decreased supporting dependency on AXL-MAPK.Conclusions: We report on a novel mechanism of AXL-MAPK-driven escape from type II JAK2 inhibition, which is targetable at different nodes. This highlights AXL as mediator of acquired resistance warranting inhibition to enhance sustainability of JAK2 inhibition in MPN

2023-11-07 | PXD039419 | Pride

Effect of cortistatin A (CA) on enhancer occupancy in CA-sensitive and -insensitive human cell lines

Project description:We characterized the marine natural product cortistatin A (CA) as an inhibitor of CDK8 to determine whether pharmacologic inhibition of CDK8 regulates super-enhancer function and inhibits AML proliferation. In this series, we use ChIP-seq of H3K27ac, H3K4me1, MED1, CDK8, BRD4, and RNA polymerase II (PolII) to examine enhancer occupancy and transcriptional response to CA in human cells lines.

2015-09-25 | GSE65138 | GEO

Effect in HCT116 cells of 3hr cortistatin A treatment on gene expression.

Project description:We characterized the marine natural product cortistatin A (CA) as an inhibitor of CDK8 to determine whether pharmacologic inhibition of CDK8 regulates super-enhancer function and inhibits AML proliferation. In this series, we examine the transcriptional effect on insensitive HCT116 cells of 3hrs exposure to CA.

2015-09-25 | GSE65030 | GEO

Effect in MOLM-14 cells of 24hr cortistatin A treatment on gene expression

Project description:We characterized the marine natural product cortistatin A (CA) as an inhibitor of CDK8 to determine whether pharmacologic inhibition of CDK8 regulates super-enhancer function and inhibits AML proliferation. In this series, we examine the transcriptional effect on MOLM-14 cells of 24hrs exposure to CA.

2015-09-25 | GSE65014 | GEO

Effect of 4hr cortistatin A treatment on gene expression in SET2 cells.

Project description:We characterized the marine natural product cortistatin A (CA) as an inhibitor of CDK8 to determine whether pharmacologic inhibition of CDK8 regulates super-enhancer function and inhibits AML proliferation. In this series, we examine the transcriptional effect on SET2 cells of 4hrs exposure to CA to identify immediate effects.

2015-09-25 | GSE65105 | GEO

Effect in MV4;11 cells of 3hr cortistatin A treatment on gene expression

Project description:We characterized the marine natural product cortistatin A (CA) as an inhibitor of CDK8 to determine whether pharmacologic inhibition of CDK8 regulates super-enhancer function and inhibits AML proliferation. In this series, we examine the transcriptional effect on MV4;11 cells of 3hrs exposure to CA to identify immediate effects.

2015-09-25 | GSE65019 | GEO

Effect in K562 cells of 3hr cortistatin A treatment on gene expression

Project description:We characterized the marine natural product cortistatin A (CA) as an inhibitor of CDK8 to determine whether pharmacologic inhibition of CDK8 regulates super-enhancer function and inhibits AML proliferation. In this series, we examine the transcriptional effect on K562 cells of 3hrs exposure to CA to identify immediate effects.

2015-09-25 | GSE65012 | GEO

Effect in MOLM-14 cells of 3hr cortistatin A treatment on gene expression

Project description:We characterized the marine natural product cortistatin A (CA) as an inhibitor of CDK8 to determine whether pharmacologic inhibition of CDK8 regulates super-enhancer function and inhibits AML proliferation. In this series, we examine the transcriptional effect on MOLM-14 cells of 3hrs exposure to CA to identify immediate effects.

2015-09-25 | GSE65015 | GEO

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