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Cancer Cell. 2016 Nov 14;30(5):764-778. doi: 10.1016/j.ccell.2016.10.002.

A Druggable TCF4- and BRD4-Dependent Transcriptional Network Sustains Malignancy in Blastic Plasmacytoid Dendritic Cell Neoplasm.

Author information

1
Lymphoid Malignancies Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA; Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Bethesda, MD 20892, USA.
2
Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA.
3
Lymphoid Malignancies Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
4
Biometric Research Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
5
Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
6
Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA 91010, USA.
7
Division of Bioinformatics and Biostatistics, NCTR/FDA, Jefferson, AR 72079, USA.
8
Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Bethesda, MD 20892, USA.
9
R&D Laboratory, EFS Rhone-Alpes Grenoble, La Tronche 38701, France; Institute for Advanced Biosciences UGA, INSERM U1209, CNRS UMR 5309, Grenoble 38000, France.
10
Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA; Department of Pathology, New York University School of Medicine, New York, NY 10016, USA. Electronic address: boris.reizis@nyumc.org.
11
Lymphoid Malignancies Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA. Electronic address: lstaudt@mail.nih.gov.

Abstract

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive and largely incurable hematologic malignancy originating from plasmacytoid dendritic cells (pDCs). Using RNAi 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 gene expression program and apoptosis. High-throughput drug screening revealed that bromodomain and extra-terminal domain inhibitors (BETis) induced BPDCN apoptosis, which was attributable to disruption of a BPDCN-specific transcriptional network controlled by TCF4-dependent super-enhancers. BETis retarded the growth of BPDCN xenografts, supporting their clinical evaluation in this recalcitrant malignancy.

KEYWORDS:

BPDCN; BRD4; HTS; TCF4; super-enhancer

PMID:
27846392
PMCID:
PMC5175469
DOI:
10.1016/j.ccell.2016.10.002
[Indexed for MEDLINE]
Free PMC Article

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