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Series GSE50622 Query DataSets for GSE50622
Status Public on Dec 23, 2013
Title Targeting transcriptional dependencies in cancer using a covalent CDK7 inhibitor (ChIP-Seq)
Organism Homo sapiens
Experiment type Genome binding/occupancy profiling by high throughput sequencing
Summary Cyclin-dependent kinase 7 (CDK7) plays a critical role in the general regulation of RNA polymerase II-mediated transcription. However, the absence of selective CDK7 inhibitors has hindered the ability to investigate the consequences of acute and prolonged inhibition of CDK7 under normal and pathological conditions. Here we present the discovery and characterization of the first covalent CDK7 inhibitor, CDK7-IN-1, that has the unprecedented ability to target a unique cysteine residue located outside of the canonical kinase domain, providing an unanticipated means of achieving selectivity for CDK7 amongst the 20 known CDKs. Cancer cell line profiling indicates that a subset of cancer cell lines, including T-cell acute lymphoblastic leukemia (T-ALL), exhibit 100-fold greater sensitivity to CDK7-IN-1 over other tumor and normal cell lines. Genome-wide expression analysis in Jurkat T-ALL indicates that CDK7-IN-1 disproportionally affects RUNX1 as well as other components of the TAL1 transcriptional network and its targets, downregulating key regulators of transcription and apoptosis critical for the T-ALL state. These oncogenes are encoded by short-lived mRNA transcripts, are associated with super-enhancers, and exhibit a strong dependency on continuous transcription for sustained expression. Therefore, pharmacological modulation of CDK7 kinase activity may define a method for the identification and treatment of tumor types exhibiting extreme dependencies on transcription for maintenance of the oncogenic state.
Overall design Jurkat, MM1S, Loucy, and HeLa (WT and Dox-inducible CDK7 mutant) cells were treated with various drugs including a covalent inhibitor of CDK7 (CDK7-IN-1), a reversible inhibitor of CDK7 (CDK7-IN-1), Flavopiridol, Actinomycin D, and DMSO controls. Replicates are annotated.
Contributor(s) Kwiatkowski NP, Zhang T, Rahl PB, Abraham BJ, Reddy J, Ficarro S, Dastur A, Ramaswamy S, Amzallag A, Tesar B, Jenkins CR, Hannett NM, McMillin D, Sanda T, Sim T, Kim ND, Look T, Mitsiades C, Weng AP, Brown JR, Benes CH, Marto J, Young RA, Gray NS
Citation(s) 25043025
Submission date Sep 05, 2013
Last update date May 15, 2019
Contact name Richard A Young
Phone 617-258-5219
Organization name Whitehead Institute for Biomedical Research
Lab Young Lab
Street address 9 Cambridge Center
City Cambridge
State/province MA
ZIP/Postal code 02142
Country USA
Platforms (2)
GPL9115 Illumina Genome Analyzer II (Homo sapiens)
GPL11154 Illumina HiSeq 2000 (Homo sapiens)
Samples (13)
GSM1224781 Pol2_Jurkat_DMSO_12hr_ChipSeq
GSM1224783 Jurkat_DMSO_WCE_ChipSeq
GSM1224784 RNAPol2_Jurkat_DMSO_6hr_ChipSeq
This SubSeries is part of SuperSeries:
GSE50625 Targeting transcriptional dependencies in cancer using a covalent CDK7 inhibitor
BioProject PRJNA218106
SRA SRP029600

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE50622_RAW.tar 1.0 Gb (http)(custom) TAR (of WIG)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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