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CDK7 inhibition interdicts deregulated transcription and cell cycle control in multiple myeloma

ABSTRACT: CDK7 inhibition interdicts deregulated transcription and cell cycle control in multiple myeloma

PROVIDER: PRJNA723314 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14287600.fastq.gz	Fastqsanger.gz
	SRR14287601.fastq.gz	Fastqsanger.gz
	SRR14287602.fastq.gz	Fastqsanger.gz
	SRR14287603.fastq.gz	Fastqsanger.gz
	SRR14287604.fastq.gz	Fastqsanger.gz

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CDK7 inhibition interdicts deregulated transcription and cell cycle control in multiple myeloma [Sensitive_MM_Cell_Lines_RNA-seq]

Project description:Cyclin dependent kinases (CDKs) are high value therapeutical targets owing to their important roles in regulating transcription and the cell cycle — two pathways commonly altered in cancer and especially in multiple myeloma (MM). Among CDKs, CDK7 uniquely bridges cell cycle and transcriptional control by activating other cell cycle CDKs and forming the general transcription factor TFIIH. Utilizing a recently developed highly selective covalent inhibitor of CDK7, we demonstrate that CDK7 inhibition elicits a strong therapeutic response in MM blocking proliferation in vitro and driving tumor regression and prolonged survival in vivo. CDK7 inhibition counteracts molecular hallmarks of deregulated cell cycle control at the G1/S checkpoint. Additionally, we show CDK7 inhibition selectively downregulates oncogenic E2F and cell cycle gene expression programs. Combination treatment with JQ1 which target oncogenic enhancer driven gene expression programs proved highly synergistic. These results support CDK7 as an attractive and therapeutically actionable molecular vulnerability in MM. Cell count normalized RNA-seq in Sensitive MM cell lines (H929 and MM1S; 24 total samples; 3 technical replicates) upon treatment with the selective covalent CDK7 inhibitor YKL-5-124 Mariateresa,Fulciniti Nikhil,Munshi

2022-04-01 | GSE172444 | GEO

CDK7 inhibition interdicts deregulated transcription and cell cycle control in multiple myeloma [Resistant_MM_Cell_Lines_24Hr_RNA-seq]

Project description:Cyclin dependent kinases (CDKs) are high value therapeutical targets owing to their important roles in regulating transcription and the cell cycle — two pathways commonly altered in cancer and especially in multiple myeloma (MM). Among CDKs, CDK7 uniquely bridges cell cycle and transcriptional control by activating other cell cycle CDKs and forming the general transcription factor TFIIH. Utilizing a recently developed highly selective covalent inhibitor of CDK7, we demonstrate that CDK7 inhibition elicits a strong therapeutic response in MM blocking proliferation in vitro and driving tumor regression and prolonged survival in vivo. CDK7 inhibition counteracts molecular hallmarks of deregulated cell cycle control at the G1/S checkpoint. Additionally, we show CDK7 inhibition selectively downregulates oncogenic E2F and cell cycle gene expression programs. Combination treatment with JQ1 which target oncogenic enhancer driven gene expression programs proved highly synergistic. These results support CDK7 as an attractive and therapeutically actionable molecular vulnerability in MM. Cell count normalized RNA-seq in Resistant MM cell lines (XG1 and AMO1; 18 total samples; 3 technical replicates) upon treatment with the selective covalent CDK7 inhibitor YKL-5-124 Mariateresa,Fulciniti Nikhil,Munshi

2022-04-01 | GSE172443 | GEO

CDK7 inhibition interdicts deregulated transcription and cell cycle control in multiple myeloma [Resistant_MM_Cell_Lines_6Hr_RNA-seq]

Project description:Cyclin dependent kinases (CDKs) are high value therapeutical targets owing to their important roles in regulating transcription and the cell cycle — two pathways commonly altered in cancer and especially in multiple myeloma (MM). Among CDKs, CDK7 uniquely bridges cell cycle and transcriptional control by activating other cell cycle CDKs and forming the general transcription factor TFIIH. Utilizing a recently developed highly selective covalent inhibitor of CDK7, we demonstrate that CDK7 inhibition elicits a strong therapeutic response in MM blocking proliferation in vitro and driving tumor regression and prolonged survival in vivo. CDK7 inhibition counteracts molecular hallmarks of deregulated cell cycle control at the G1/S checkpoint. Additionally, we show CDK7 inhibition selectively downregulates oncogenic E2F and cell cycle gene expression programs. Combination treatment with JQ1 which target oncogenic enhancer driven gene expression programs proved highly synergistic. These results support CDK7 as an attractive and therapeutically actionable molecular vulnerability in MM. Cell count normalized RNA-seq in Resistant MM cell lines (XG1 and AMO1; 18 total samples; 3 technical replicates) upon treatment with the selective covalent CDK7 inhibitor YKL-5-124 Mariateresa,Fulciniti Nikhil,Munshi

2022-04-01 | GSE172442 | GEO

CDK7 inhibition interdicts deregulated transcription and cell cycle control in multiple myeloma [Sensitive_MM_Cell_Lines_RNA-seq]

Project description:CDK7 inhibition interdicts deregulated transcription and cell cycle control in multiple myeloma [Sensitive_MM_Cell_Lines_RNA-seq]

| PRJNA723316 | ENA

CDK7 inhibition interdicts deregulated transcription and cell cycle control in multiple myeloma [Resistant_MM_Cell_Lines_24Hr_RNA-seq]

Project description:CDK7 inhibition interdicts deregulated transcription and cell cycle control in multiple myeloma [Resistant_MM_Cell_Lines_24Hr_RNA-seq]

| PRJNA723317 | ENA

CDK7 inhibition interdicts deregulated transcription and cell cycle control in multiple myeloma [Resistant_MM_Cell_Lines_6Hr_RNA-seq]

Project description:CDK7 inhibition interdicts deregulated transcription and cell cycle control in multiple myeloma [Resistant_MM_Cell_Lines_6Hr_RNA-seq]

| PRJNA723318 | ENA

CDK7 inhibition interdicts deregulated transcription and cell cycle control in multiple myeloma

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-04-01 | GSE172445 | GEO

CDK7 controls E2F- and MYC-driven proliferative and metabolic vulnerabilities in multiple myeloma

Project description:Therapeutic targeting of CDK7 has proven beneficial in pre-clinical studies, yet the off-target effects of currently available CDK7 inhibitors make it difficult to pinpoint the exact mechanisms behind MM cell death mediated by CDK7 inhibition. Here, we show that CDK7 expression positively correlates with E2F and MYC transcriptional programs in multiple myeloma (MM) patient cells; and its selective targeting counteracts E2F activity via perturbation of the CDKs/Rb axis and impairs MYC-regulated metabolic gene signatures translating into defects in glycolysis and reduced levels of lactate production in MM cells. CDK7 inhibition using the covalent small molecule inhibitor YKL-5-124 elicits a strong therapeutic response with minimal effects on normal cells, and causes in vivo tumor regression increasing survival in several MM mouse models including a genetically engineered mouse model of MYC-dependent MM. Through its role as a critical cofactor and regulator of MYC and E2F activity, CDK7 is therefore a master regulator of oncogenic cellular programs supporting MM growth and survival, and a valuable therapeutic target providing rationale for development of YKL-5-124 for clinical use.

2023-02-01 | GSE172441 | GEO

Effects of CDK7 inhibition on fibrotic gene expression

Project description:Targeted CDK7, a cyclin-dependent kinase with dual functionality in both cell cycle and transcription, by small molecule inhibitors may attenuate fibrotic response both in vivo and in vitro. However, the exact role of CDK7 in this pathogenic process remains quite elusive. Herein, we want to address this MOA question using RNA-seq. In this RNA-seq experiment we set out to determine (1) the role of CDK7 in fibroblast gene expression and (2) the role of CDK7 in TGF beta-driven gene expression in normal human lung fibroblasts.

2024-11-06 | GSE277437 | GEO

Super-enhancer profiling combined with CDK7 inhibition-transcripts identifies novel oncogenes of multiple myeloma.

Project description:Super-enhancer profiling combined with CDK7 inhibition-transcripts identifies novel oncogenes of multiple myeloma.

| PRJNA608768 | ENA