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| 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
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| 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.
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| 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.
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| 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 |
| E-mail(s) |
young_computation@wi.mit.edu
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| Phone |
617-258-5219
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| Organization name |
Whitehead Institute for Biomedical Research
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| Lab |
Young Lab
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| Street address |
9 Cambridge Center
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| City |
Cambridge |
| State/province |
MA |
| ZIP/Postal code |
02142 |
| Country |
USA |
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| Platforms (2) |
| GPL9115 |
Illumina Genome Analyzer II (Homo sapiens) |
| GPL11154 |
Illumina HiSeq 2000 (Homo sapiens) |
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| Samples (13)
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| This SubSeries is part of SuperSeries: |
| GSE50625 |
Targeting transcriptional dependencies in cancer using a covalent CDK7 inhibitor |
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| Relations |
| BioProject |
PRJNA218106 |
| SRA |
SRP029600 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE50622_RAW.tar |
1.0 Gb |
(http)(custom) |
TAR (of WIG) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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