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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 (ATAC-Seq) |
Organism |
Homo sapiens |
Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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Summary |
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive and largely incurable hematologic malignancy originating from plasmacytoid dendritic cells (pDCs). Using RNA interference screening, we identified the E-box transcription factor TCF4 as a master regulator of the BPDCN oncogenic program. TCF4 served as a faithful diagnostic marker of BPDCN, and its downregulation caused the loss of the BPDCN-specific expression program and apoptosis. High-throughput drug screening revealed that bromodomain and extra-terminal domain inhibitors (BETi's) induce BPDCN apoptosis, which was attributable to disruption of the TCF4-dependent transcriptional network and loss of BPDCN-specific super-enhancers. BETi's retarded the growth of BPDCN xenografts, supporting their clinical evaluation in this recalcitrant malignancy.
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Overall design |
We performed ATAC-Seq to measure chromatin accessibility in normal pDCs (n=2) and primary BPDCN (n=1), together with BPDCN cell lines (Cal-1 and Gen2.2) (n=2), AML cell lines (HL-60 and MOLM-14) (n=2) and conventional myeloid DCs (n=2) as specificity controls.
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Citation(s) |
27846392 |
Submission date |
Jul 20, 2016 |
Last update date |
May 15, 2019 |
Contact name |
Louis M. Staudt |
E-mail(s) |
lstaudt@mail.nih.gov
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Phone |
301-402-1892
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Organization name |
National Cancer Institute
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Department |
Lymphoid Malignancies Branch
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Lab |
Louis M Staudt
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Street address |
9000 Rockville Pike, Bldg 10, Rm 4N114
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City |
Bethesda |
State/province |
MD |
ZIP/Postal code |
20892 |
Country |
USA |
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Platforms (1) |
GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
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Samples (9)
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Relations |
BioProject |
PRJNA330681 |
SRA |
SRP078993 |