title: A Druggable TCF4- and BRD4-Dependent Transcriptional Network Sustains Malignancy in Blastic Plasmacytoid Dendritic Cell Neoplasm.
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.
authors.affiliation: 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.
authors.forename: Michele
authors.initials: M
authors.lastname: Ceribelli
authors.affiliation: Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Zhiying Esther
authors.initials: ZE
authors.lastname: Hou
authors.affiliation: Lymphoid Malignancies Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Priscilla N
authors.initials: PN
authors.lastname: Kelly
authors.affiliation: Lymphoid Malignancies Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Da Wei
authors.initials: DW
authors.lastname: Huang
authors.affiliation: Biometric Research Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: George
authors.initials: G
authors.lastname: Wright
authors.affiliation: Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Karthik
authors.initials: K
authors.lastname: Ganapathi
authors.affiliation: Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Moses O
authors.initials: MO
authors.lastname: Evbuomwan
authors.affiliation: Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Stefania
authors.initials: S
authors.lastname: Pittaluga
authors.affiliation: Lymphoid Malignancies Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Shaffer
authors.affiliation: Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA 91010, USA.
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
authors.affiliation: Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA 91010, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Forman
authors.affiliation: Division of Bioinformatics and Biostatistics, NCTR/FDA, Jefferson, AR 72079, USA.
authors.forename: Wenming
authors.initials: W
authors.lastname: Xiao
authors.affiliation: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Bethesda, MD 20892, USA.
authors.forename: Rajarshi
authors.initials: R
authors.lastname: Guha
authors.affiliation: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Bethesda, MD 20892, USA.
authors.forename: Xiaohu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Bethesda, MD 20892, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Ferrer
authors.affiliation: R&D Laboratory, EFS Rhone-Alpes Grenoble, La Tronche 38701, France; Institute for Advanced Biosciences UGA, INSERM U1209, CNRS UMR 5309, Grenoble 38000, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Chaperot
authors.affiliation: R&D Laboratory, EFS Rhone-Alpes Grenoble, La Tronche 38701, France; Institute for Advanced Biosciences UGA, INSERM U1209, CNRS UMR 5309, Grenoble 38000, France.
authors.forename: Joel
authors.initials: J
authors.lastname: Plumas
authors.affiliation: Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Elaine S
authors.initials: ES
authors.lastname: Jaffe
authors.affiliation: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Bethesda, MD 20892, USA.
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Thomas
authors.affiliation: 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.
authors.forename: Boris
authors.initials: B
authors.lastname: Reizis
authors.affiliation: Lymphoid Malignancies Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA. Electronic address: lstaudt@mail.nih.gov.
authors.forename: Louis M
authors.initials: LM
authors.lastname: Staudt
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000378:metabolism / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D018922:HL-60 Cells; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000494:pharmacology; D054852:Small Molecule Libraries / Q000008:administration & dosage* / Q000494:pharmacology; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays; D000092468:Bromodomain Containing Proteins
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D054852:Small Molecule Libraries; D000073940:Transcription Factor 4; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C532096:TCF4 protein, human
keywords: BPDCN; BRD4; HTS; TCF4; super-enhancer