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

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

PROVIDER: PRJNA723317 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14287563.fastq.gz	Fastqsanger.gz
	SRR14287564.fastq.gz	Fastqsanger.gz
	SRR14287565.fastq.gz	Fastqsanger.gz
	SRR14287566.fastq.gz	Fastqsanger.gz
	SRR14287567.fastq.gz	Fastqsanger.gz

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

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

| PRJNA723314 | ENA

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: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]

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: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 [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 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

Multiple myeloma

Project description:Multiple myeloma

| PRJNA515992 | ENA

Proteogenomic landscape of multiple myeloma

Project description:Multiple myeloma is a plasma cell malignancy of the bone marrow. Despite therapeutic advances, multiple myeloma remains incurable and better risk stratification as well as new therapies are therefore highly needed. The proteome of multiple myeloma has not been systematically assessed before and holds the potential to uncover additional insight into disease biology and improved prognostic models. Here, we provide a comprehensive multi-omics analysis including deep tandem mass tags (TMT)-based quantitative global (phospho)proteomics, RNA sequencing and nanopore DNA sequencing of 138 primary patient-derived plasma cell malignancies encompassing treatment-naive multiple myeloma patients treated in clinical trials, plasma cell leukemia, and the premalignancy monoclonal gammopathy of undetermined significance (MGUS), as well as healthy controls. We found that the (phospho)proteome of malignant plasma cells is highly deregulated as compared to healthy plasma cells and is both defined by chromosomal alterations and extensive post-transcriptional regulation. A protein signature was identified that is associated with aggressive disease and more predictive for outcome than cytogenetic-based risk assessment in newly diagnosed multiple myeloma. Integration with functional genetics and single-cell sequencing revealed generally and genetic subtype-specific deregulated proteins and pathways in plasma cell malignancies that include novel potential targets for (immuno)therapies. These findings provide new insights in the biology of multiple myeloma and will be a unique resource for investigating new therapeutic approaches.

2024-07-09 | PXD038437 | Pride

Proteogenomic landscape of multiple myeloma

Project description:Multiple myeloma is a plasma cell malignancy of the bone marrow. Despite therapeutic advances, multiple myeloma remains incurable and better risk stratification as well as new therapies are therefore highly needed. The proteome of multiple myeloma has not been systematically assessed before and holds the potential to uncover additional insight into disease biology and improved prognostic models. Here, we provide a comprehensive multi-omics analysis including deep tandem mass tag (TMT)-based quantitative global (phospho)proteomics, RNA sequencing and nanopore DNA sequencing of 138 primary patient-derived plasma cell malignancies encompassing treatment-naive multiple myeloma patients treated in clinical trials, plasma cell leukemia, and the premalignancy monoclonal gammopathy of undetermined significance (MGUS), as well as healthy controls. We found that the (phospho)proteome of malignant plasma cells is highly deregulated as compared to healthy plasma cells and is both defined by chromosomal alterations and extensive post-transcriptional regulation. A protein signature was identified that is associated with aggressive disease and more predictive for outcome than cytogenetic-based risk assessment in newly diagnosed multiple myeloma. Integration with functional genetics and single-cell sequencing revealed generally and genetic subtype-specific deregulated proteins and pathways in plasma cell malignancies that include novel potential targets for (immuno)therapies. These findings provide new insights in the biology of multiple myeloma and will be a unique resource for investigating new therapeutic approaches.

2024-07-09 | PXD043580 | Pride

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