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

Michele Ceribelli; Zhiying Esther Hou; Priscilla N Kelly; Da Wei Huang; George Wright; Karthik Ganapathi; Moses O Evbuomwan; Stefania Pittaluga; Arthur L Shaffer; Guido Marcucci; Stephen J Forman; Wenming Xiao; Rajarshi Guha; Xiaohu Zhang; Marc Ferrer; Laurence Chaperot; Joel Plumas; Elaine S Jaffe; Craig J Thomas; Boris Reizis; Louis M Staudt

doi:10.1016/j.ccell.2016.10.002

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

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

Authors

Michele Ceribelli¹, Zhiying Esther Hou², Priscilla N Kelly³, Da Wei Huang³, George Wright⁴, Karthik Ganapathi⁵, Moses O Evbuomwan⁵, Stefania Pittaluga⁵, Arthur L Shaffer³, Guido Marcucci⁶, Stephen J Forman⁶, Wenming Xiao⁷, Rajarshi Guha⁸, Xiaohu Zhang⁸, Marc Ferrer⁸, Laurence Chaperot⁹, Joel Plumas⁹, Elaine S Jaffe⁵, Craig J Thomas⁸, Boris Reizis¹⁰, Louis M Staudt¹¹

Affiliations

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.

Published by Elsevier Inc.

MeSH terms

Animals
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / antagonists & inhibitors
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics*
Cell Cycle Proteins
Cell Line, Tumor
Dendritic Cells / metabolism
Dendritic Cells / pathology*
Gene Expression Regulation, Neoplastic
Gene Regulatory Networks
HL-60 Cells
Hematologic Neoplasms / drug therapy*
Hematologic Neoplasms / genetics
Hematologic Neoplasms / pathology
Humans
Jurkat Cells
Mice
Nuclear Proteins / genetics*
RNA, Small Interfering / administration & dosage*
RNA, Small Interfering / pharmacology
Small Molecule Libraries / administration & dosage*
Small Molecule Libraries / pharmacology
Transcription Factor 4
Transcription Factors / antagonists & inhibitors
Transcription Factors / genetics*
Xenograft Model Antitumor Assays

Substances

BRD4 protein, human
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
Cell Cycle Proteins
Nuclear Proteins
RNA, Small Interfering
Small Molecule Libraries
TCF4 protein, human
Transcription Factor 4
Transcription Factors

Abstract

MeSH terms

Substances

Grants and funding