title: Haploinsufficiency for NR3C1, the gene encoding the glucocorticoid receptor, in blastic plasmacytoid dendritic cell neoplasms.
abstract: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and highly aggressive leukemia for which knowledge on disease mechanisms and effective therapies are currently lacking. Only a handful of recurring genetic mutations have been identified and none is specific to BPDCN. In this study, through molecular cloning in an index case that presented a balanced t(3;5)(q21;q31) and molecular cytogenetic analyses in a further 46 cases, we identify monoallelic deletion of NR3C1 (5q31), encoding the glucocorticoid receptor (GCR), in 13 of 47 (28%) BPDCN patients. Targeted deep sequencing in 36 BPDCN cases, including 10 with NR3C1 deletion, did not reveal NR3C1 point mutations or indels. Haploinsufficiency for NR3C1 defined a subset of BPDCN with lowered GCR expression and extremely poor overall survival (P = .0006). Consistent with a role for GCR in tumor suppression, functional analyses coupled with gene expression profiling identified corticoresistance and loss-of-EZH2 function as major downstream consequences of NR3C1 deletion in BPDCN. Subsequently, more detailed analyses of the t(3;5)(q21;q31) revealed fusion of NR3C1 to a long noncoding RNA (lncRNA) gene (lincRNA-3q) that encodes a novel, nuclear, noncoding RNA involved in the regulation of leukemia stem cell programs and G1/S transition, via E2F. Overexpression of lincRNA-3q was a consistent feature of malignant cells and could be abrogated by bromodomain and extraterminal domain (BET) protein inhibition. Taken together, this work points to NR3C1 as a haploinsufficient tumor suppressor in a subset of BPDCN and identifies BET inhibition, acting at least partially via lncRNA blockade, as a novel treatment option in BPDCN.
authors.affiliation: INSERM U1209, CNRS UMR 5309, Faculté de Médecine, Université Grenoble Alpes, Institut Albert Bonniot, Grenoble, France;
authors.forename: Anouk
authors.initials: A
authors.lastname: Emadali
authors.affiliation: INSERM U1209, CNRS UMR 5309, Faculté de Médecine, Université Grenoble Alpes, Institut Albert Bonniot, Grenoble, France;
authors.forename: Neda
authors.initials: N
authors.lastname: Hoghoughi
authors.affiliation: INSERM U1209, CNRS UMR 5309, Faculté de Médecine, Université Grenoble Alpes, Institut Albert Bonniot, Grenoble, France;
authors.forename: Samuel
authors.initials: S
authors.lastname: Duley
authors.affiliation: INSERM U1209, CNRS UMR 5309, Faculté de Médecine, Université Grenoble Alpes, Institut Albert Bonniot, Grenoble, France;
authors.forename: Azadeh
authors.initials: A
authors.lastname: Hajmirza
authors.affiliation: International Center for Infectiology Research, Université de Lyon 1, Lyon, France; INSERM U1111, CNRS UMR 5308, Ecole Normale Supérieure de Lyon, Lyon, France; INSERM U1065, Centre Méditerranéen de Médecine Moléculaire, Nice, France;
authors.forename: Els
authors.initials: E
authors.lastname: Verhoeyen
authors.affiliation: International Center for Infectiology Research, Université de Lyon 1, Lyon, France; INSERM U1111, CNRS UMR 5308, Ecole Normale Supérieure de Lyon, Lyon, France;
authors.forename: Francois-Loic
authors.initials: FL
authors.lastname: Cosset
authors.affiliation: INSERM U918, Département d'Hématologie, Université de Rouen, Centre Henri Becquerel, Rouen, France;
authors.forename: Philippe
authors.initials: P
authors.lastname: Bertrand
authors.affiliation: Institut d'Hématologie, Centre Hospitalier Régional Universitaire de Lille, Lille, France;
authors.forename: Christophe
authors.initials: C
authors.lastname: Roumier
authors.affiliation: INSERM U645, Etablissement français du sang, Université de Franche-Comté, Besançon, France;
authors.forename: Anne
authors.initials: A
authors.lastname: Roggy
authors.affiliation: Labortoire de Génétique Onco-Hématologique and.
authors.forename: Céline
authors.initials: C
authors.lastname: Suchaud-Martin
authors.affiliation: INSERM U1209, CNRS UMR 5309, Faculté de Médecine, Université Grenoble Alpes, Institut Albert Bonniot, Grenoble, France; Labortoire de Génétique Onco-Hématologique and.
authors.forename: Martine
authors.initials: M
authors.lastname: Chauvet
authors.affiliation: INSERM U1209, CNRS UMR 5309, Faculté de Médecine, Université Grenoble Alpes, Institut Albert Bonniot, Grenoble, France;
authors.forename: Sarah
authors.initials: S
authors.lastname: Bertrand
authors.affiliation: INSERM U1209, CNRS UMR 5309, Faculté de Médecine, Université Grenoble Alpes, Institut Albert Bonniot, Grenoble, France; Labortoire de Génétique Onco-Hématologique and.
authors.forename: Sieme
authors.initials: S
authors.lastname: Hamaidia
authors.affiliation: INSERM U1209, CNRS UMR 5309, Faculté de Médecine, Université Grenoble Alpes, Institut Albert Bonniot, Grenoble, France;
authors.forename: Sophie
authors.initials: S
authors.lastname: Rousseaux
authors.affiliation: INSERM U1209, CNRS UMR 5309, Faculté de Médecine, Université Grenoble Alpes, Institut Albert Bonniot, Grenoble, France;
authors.forename: Véronique
authors.initials: V
authors.lastname: Josserand
authors.affiliation: INSERM U1209, CNRS UMR 5309, Faculté de Médecine, Université Grenoble Alpes, Institut Albert Bonniot, Grenoble, France; Departement de Dermatologie, Centre Hospitalier et Universitaire de Grenoble-Alpes, Grenoble, France;
authors.forename: Julie
authors.initials: J
authors.lastname: Charles
authors.affiliation: Departement de Dermatologie, Centre Hospitalier et Universitaire de Grenoble-Alpes, Grenoble, France;
authors.forename: Isabelle
authors.initials: I
authors.lastname: Templier
authors.affiliation: Department of Community Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan;
authors.forename: Takahiro
authors.initials: T
authors.lastname: Maeda
authors.affiliation: INSERM U1209, CNRS UMR 5309, Faculté de Médecine, Université Grenoble Alpes, Institut Albert Bonniot, Grenoble, France; Etablissement français du sang Rhône-Alpes, Laboratoire de recherche et développement, Grenoble, France;
authors.forename: Juliana
authors.initials: J
authors.lastname: Bruder-Costa
authors.affiliation: INSERM U1209, CNRS UMR 5309, Faculté de Médecine, Université Grenoble Alpes, Institut Albert Bonniot, Grenoble, France; Etablissement français du sang Rhône-Alpes, Laboratoire de recherche et développement, Grenoble, France;
authors.forename: Laurence
authors.initials: L
authors.lastname: Chaperot
authors.affiliation: INSERM U1209, CNRS UMR 5309, Faculté de Médecine, Université Grenoble Alpes, Institut Albert Bonniot, Grenoble, France; Etablissement français du sang Rhône-Alpes, Laboratoire de recherche et développement, Grenoble, France;
authors.forename: Joel
authors.initials: J
authors.lastname: Plumas
authors.affiliation: INSERM U1209, CNRS UMR 5309, Faculté de Médecine, Université Grenoble Alpes, Institut Albert Bonniot, Grenoble, France; Laboratoire d'Immunologie and.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Jacob
authors.affiliation: INSERM U1209, CNRS UMR 5309, Faculté de Médecine, Université Grenoble Alpes, Institut Albert Bonniot, Grenoble, France;
authors.forename: Thierry
authors.initials: T
authors.lastname: Bonnefoix
authors.affiliation: Departement d'Hématologie Clinique, Centre Hospitalier et Universitaire de Grenoble-Alpes, Grenoble, France;
authors.forename: Sophie
authors.initials: S
authors.lastname: Park
authors.affiliation: INSERM U1209, CNRS UMR 5309, Faculté de Médecine, Université Grenoble Alpes, Institut Albert Bonniot, Grenoble, France; Departement d'Hématologie Clinique, Centre Hospitalier et Universitaire de Grenoble-Alpes, Grenoble, France;
authors.forename: Remy
authors.initials: R
authors.lastname: Gressin
authors.affiliation: Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands;
authors.forename: Cornelis P
authors.initials: CP
authors.lastname: Tensen
authors.affiliation: Department of Medicine, Perugia University, Perugia, Italy;
authors.forename: Cristina
authors.initials: C
authors.lastname: Mecucci
authors.affiliation: Laboratory of Oncohematology, Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants-Malades, University Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades, INSERM U1151, Paris, France;
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Macintyre
authors.affiliation: INSERM U1209, CNRS UMR 5309, Faculté de Médecine, Université Grenoble Alpes, Institut Albert Bonniot, Grenoble, France; Labortoire de Génétique Onco-Hématologique and.
authors.forename: Dominique
authors.initials: D
authors.lastname: Leroux
authors.affiliation: INSERM U1209, CNRS UMR 5309, Faculté de Médecine, Université Grenoble Alpes, Institut Albert Bonniot, Grenoble, France;
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Brambilla
authors.affiliation: Unité Fonctionnelle de Cytogénétique Hématologique, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; and.
authors.forename: Florence
authors.initials: F
authors.lastname: Nguyen-Khac
authors.affiliation: Laboratoire d'Hématologie, Pôle de biologie, Centre Hospitalier et Universitaire de Toulouse, Toulouse, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Luquet
authors.affiliation: INSERM U918, Département d'Hématologie, Université de Rouen, Centre Henri Becquerel, Rouen, France;
authors.forename: Dominique
authors.initials: D
authors.lastname: Penther
authors.affiliation: INSERM U918, Département d'Hématologie, Université de Rouen, Centre Henri Becquerel, Rouen, France;
authors.forename: Christian
authors.initials: C
authors.lastname: Bastard
authors.affiliation: INSERM U918, Département d'Hématologie, Université de Rouen, Centre Henri Becquerel, Rouen, France;
authors.forename: Fabrice
authors.initials: F
authors.lastname: Jardin
authors.affiliation: INSERM U1209, CNRS UMR 5309, Faculté de Médecine, Université Grenoble Alpes, Institut Albert Bonniot, Grenoble, France; Labortoire de Génétique Onco-Hématologique and.
authors.forename: Christine
authors.initials: C
authors.lastname: Lefebvre
authors.affiliation: INSERM U645, Etablissement français du sang, Université de Franche-Comté, Besançon, France;
authors.forename: Francine
authors.initials: F
authors.lastname: Garnache
authors.affiliation: INSERM U1209, CNRS UMR 5309, Faculté de Médecine, Université Grenoble Alpes, Institut Albert Bonniot, Grenoble, France; Labortoire de Génétique Onco-Hématologique and.
authors.forename: Mary B
authors.initials: MB
authors.lastname: Callanan
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D003713:Dendritic Cells / Q000378:metabolism / Q000473:pathology*; D015973:Gene Expression Regulation, Leukemic; D057895:Haploinsufficiency; D006801:Humans; D007938:Leukemia / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D062085:RNA, Long Noncoding / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000737:chemistry / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D014407:Tumor Cells, Cultured; D055815:Young Adult
chemical_list: C497713:NR3C1 protein, human; D062085:RNA, Long Noncoding; D011965:Receptors, Glucocorticoid