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CDK7 inhibitor THZ1 induces the cell apoptosis of B-cell acute lymphocytic leukemia by perturbing cellular metabolism

ABSTRACT: CDK7 inhibitor THZ1 induces the cell apoptosis of B-cell acute lymphocytic leukemia by perturbing cellular metabolism

PROVIDER: PRJNA702995 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13745073_1.fastq.gz	Fastqsanger.gz
	SRR13745073_2.fastq.gz	Fastqsanger.gz
	SRR13745074_1.fastq.gz	Fastqsanger.gz
	SRR13745074_2.fastq.gz	Fastqsanger.gz
	SRR13745075_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

CDK7 inhibitor THZ1 induces the cell apoptosis of B-cell acute lymphocytic leukemia by perturbing cellular metabolism

Project description:Purpose:CDK7 is a potential drug target for the treatment of tumors. THZ1 is the first selective and covalent CDK7 inhibitor, which shows anti-tumor effects in various cancers by inhibiting cell proliferation and inducing apoptosis. However, whether THZ1 has an inhibitory effect on B-ALL cells and the underlying mechanism remains unclear. To address this question, we collected THZ1- and DMSO-treated cells for RNA sequencing Methods:Nalm6 cells were seeded at a density of 1× 10e6 cells/ml and treated with 500nm THZ1or DMSO for 24h. Results:THZ1 perturbed the cellular metabolic pathways of B-ALL cells in vitro.

2021-02-20 | GSE167099 | GEO

CDK7 Inhibitor THZ1 Induces the Cell Apoptosis of B-Cell Acute Lymphocytic Leukemia by Perturbing Cellular Metabolism.

Project description:B-cell acute lymphocytic leukemia (B-ALL) is a malignant blood cancer that develops in children and adults and leads to high mortality. THZ1, a covalent cyclin-dependent kinase 7 (CDK7) inhibitor, shows anti-tumor effects in various cancers by inhibiting cell proliferation and inducing apoptosis. However, whether THZ1 has an inhibitory effect on B-ALL cells and the underlying mechanism remains obscure. In this study, we showed that THZ1 arrested the cell cycle of B-ALL cells in vitro in a low concentration, while inducing the apoptosis of B-ALL cells in vitro in a high concentration by activating the apoptotic pathways. In addition, RNA-SEQ results revealed that THZ1 disrupted the cellular metabolic pathways of B-ALL cells. Moreover, THZ1 suppressed the cellular metabolism and blocked the production of cellular metabolic intermediates in B-ALL cells. Mechanistically, THZ1 inhibited the cellular metabolism of B-ALL by downregulating the expression of c-MYC-mediated metabolic enzymes. However, THZ1 treatment enhanced cell apoptosis in over-expressed c-MYC B-ALL cells, which was involved in the upregulation of p53 expression. Collectively, our data demonstrated that CDK7 inhibitor THZ1 induced the apoptosis of B-ALL cells by perturbing c-MYC-mediated cellular metabolism, thereby providing a novel treatment option for B-ALL.

| S-EPMC8056175 | biostudies-literature

THZ1 targeting CDK7 suppresses STAT transcriptional activity and sensitizes T-cell lymphomas to BCL2 inhibitors

Project description:Peripheral T-cell lymphomas (PTCL) are aggressive diseases with poor response to chemotherapy and dismal survival. Identification of effective strategies to target PTCL biology represents an urgent need. Here we report that PTCL are sensitive to transcription-targeting drugs, and, in particular, to THZ1, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7). The STAT-signaling pathway is highly vulnerable to THZ1 even in PTCL cells that carry the activating STAT3 mutation Y640F. In mutant cells, CDK7 inhibition decreases STAT3 chromatin binding and expression of highly transcribed target genes like MYC, PIM1, MCL1, CD30, IL2RA, CDC25A and IL4R. In surviving cells, THZ1 decreases the expression of STAT-regulated anti-apoptotic BH3 family members MCL1 and BCL-XL sensitizing PTCL cells to BH3 mimetic drugs. Accordingly, the combination of THZ1 and the BH3 mimetic obatoclax improves lymphoma growth control in a primary PTCL ex vivo culture and in two STAT3-mutant PTCL xenografts, delineating a potential targeted agent-based therapeutic option for these patients.

2016-12-15 | GSE79955 | GEO

The CDK7 Inhibitor THZ1 Alters RNA Polymerase Dynamics at the 5’ and 3’ Ends of Genes

Project description:The t(8;21) is one of the most frequent chromosomal translocations associated with acute myeloid leukemia (AML). We found that t(8;21) AML were extremely sensitive to THZ1, which triggered apoptosis after only 4 hr. We used precision nuclear run-on transcription sequencing (PROseq) to define the global effects of THZ1 and other CDK inhibitors on RNA polymerase II dynamics. Inhibition of CDK7 using THZ1 caused wide-spread loss of promoter-proximal paused RNA polymerase. This loss of 5’ pausing was associated with accumulation of polymerases in the body of a large number of genes. However, there were modest effects on genes regulated by “super-enhancers”. At the 3’ ends of genes, treatment with THZ1 suppressed RNA polymerase “read through” at the end of the last exon, which resembled a phenotype associated with a mutant RNA polymerase with slower elongation rates. Consistent with this hypothesis, polyA site-sequencing (PolyA-seq) did not detect differences in polyA sites after THZ1 treatment. PROseq analysis after short treatments with THZ1 suggested that these 3’ effects were due to altered CDK7 activity at the 5’ end of long genes, and were likely to be due to slower rates of elongation.

2019-02-11 | GSE102243 | GEO

RNA-seq analysis evaluating effects of Cdk7 inhibitor THZ1 on responses of mouse hearts to transverse aortic artery constriction (TAC)

Project description:RNA-seq analysis evaluating effects of Cdk7 inhibitor THZ1 on responses of mouse hearts to TAC

2022-04-25 | GSE151254 | GEO

RNA-seq analysis evaluating effects of Cdk7 inhibitor THZ1 on responses of neonatal rat ventricular myocytes (NRVM) to adrenergic receptor agonist phenylephrine (PE)

Project description:RNA-seq analysis evaluating effects of Cdk7 inhibitor THZ1 on responses of NRVM to adrenergic receptor agonist PE

2022-04-25 | GSE151253 | GEO

RNA polymerase II (RNAPII) ChIP-seq analysis evaluating effects of Cdk7 inhibitor THZ1 on responses of neonatal rat ventricular myocytes (NRVM) to adrenergic receptor agonist phenylephrine (PE)

Project description:RNA polymerase II (RNAPII) ChIP-seq analysis evaluating effects of Cdk7 inhibitor THZ1 on responses of NRVM to adrenergic receptor agonist PE

2022-04-25 | GSE151252 | GEO

Targeting Transcriptional Addictions in Small Cell Lung Cancer with a Covalent CDK7 Inhibitor (Affymetrix)

Project description:Small cell lung cancer (SCLC) is an aggressive disease with high mortality. The identification of effective pharmacological strategies to target SCLC biology represents an urgent need. Using a high-throughput cellular screen of a diverse chemical library we observe that SCLC is sensitive to transcription-targeting drugs, and in particular to THZ1, a newly identified covalent inhibitor of cyclin-dependent kinase 7 (CDK7). We find that expression of super-enhancer associated transcription factor genes including MYC family proto-oncogenes and neuroendocrine lineage-specific factors are highly vulnerability to THZ1 treatment. We propose that downregulation of these transcription factors contributes, in part, to SCLC sensitivity to transcriptional inhibitors and that THZ1 represents a novel treatment paradigm for targeted SCLC therapy. Microarray expression in small cell lung cancer lines treated with DMSO or THZ1

2014-10-23 | E-GEOD-62609 | biostudies-arrayexpress

Targeting of Super-Enhancer-Associated Oncogenic Transcription in MYCN-driven tumor cells by CDK7 inhibition [Gene Expression]

Project description:Global gene expression after CDK7 inhibition by THZ1 Global gene expression after genetic knockdown or overexpression of MYCN

2014-11-21 | E-GEOD-62724 | biostudies-arrayexpress

Differential gene expression analysis of MYCN-amplified neuroblastoma cells after THZ1 and TKI combination therapy.

Project description:The CDK7 inhibitor THZ1 has been shown to suppress MYCN gene transcription but not cause significant cell death as a single agent. The tyrosine kinase inhibitors (TKIs) ponatinib and lapatinib were found to exert synergistic anti-cancer effects in combination with the CDK7 inhibitor THZ1, on MYCN amplified neuroblastoma cell lines.

2020-03-20 | GSE128649 | GEO

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