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| Status |
Public on Nov 15, 2016 |
| Title |
A druggable TCF4- and BRD4-dependent transcriptional network sustains malignancy in blastic plasmacytoid dendritic cell neoplasm (ChIP-Seq) |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
|
| Summary |
We combined loss-of-function RNA interference screening and a high-throughput drug toxicity screening to define novel therapeutic targets in blastic plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive hematologic malignancy for which no curative therapy exists. The E-box transcription factor TCF4 emerged as the master transcriptional regulator of the BPDCN oncogenic program, a finding that can be exploited for the accurate molecular diagnosis of BPDCN. Genetic interference with the TCF4-dependent network induced a rewiring of BPDCN gene expression, resulting in apoptosis. Treatment of BPDCN lines with bromodomain and extra-terminal domain inhibitors (BETi's) down regulated TCF4 and its target gene network, inducing apoptosis both in vitro and retarding growth of BPDCN xenografts in vivo, supporting the clinical evaluation of BETi's in this lethal cancer.
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| Overall design |
We performed chromatin immunoprecipitation coupled to NGS (ChIP-Seq) to identify genomic binding sites for TCF4 in both cell lines, using an anti- TCF4 rabbit monoclonal antibody that we developed for this purpose. We performed BRD4 and RNA Pol2 ChIP-Seq before and after JQ1 treatment, in both the Cal-1 and Gen2.2 BPDCN lines.
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| |
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| Citation(s) |
27846392 |
| Submission date |
Dec 18, 2015 |
| Last update date |
May 15, 2019 |
| Contact name |
Louis M. Staudt |
| E-mail(s) |
lstaudt@mail.nih.gov
|
| Phone |
301-402-1892
|
| Organization name |
National Cancer Institute
|
| Department |
Lymphoid Malignancies Branch
|
| Lab |
Louis M Staudt
|
| Street address |
9000 Rockville Pike, Bldg 10, Rm 4N114
|
| City |
Bethesda |
| State/province |
MD |
| ZIP/Postal code |
20892 |
| Country |
USA |
| |
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| Platforms (2) |
| GPL10999 |
Illumina Genome Analyzer IIx (Homo sapiens) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
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| Samples (16)
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| Relations |
| BioProject |
PRJNA306431 |
| SRA |
SRP067566 |
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