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Blood. 2016 Jun 16;127(24):3040-53. doi: 10.1182/blood-2015-09-671040. Epub 2016 Apr 8.

Haploinsufficiency for NR3C1, the gene encoding the glucocorticoid receptor, in blastic plasmacytoid dendritic cell neoplasms.

Author information

1
INSERM U1209, CNRS UMR 5309, Faculté de Médecine, Université Grenoble Alpes, Institut Albert Bonniot, Grenoble, France;
2
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;
3
International Center for Infectiology Research, Université de Lyon 1, Lyon, France; INSERM U1111, CNRS UMR 5308, Ecole Normale Supérieure de Lyon, Lyon, France;
4
INSERM U918, Département d'Hématologie, Université de Rouen, Centre Henri Becquerel, Rouen, France;
5
Institut d'Hématologie, Centre Hospitalier Régional Universitaire de Lille, Lille, France;
6
INSERM U645, Etablissement français du sang, Université de Franche-Comté, Besançon, France;
7
Labortoire de Génétique Onco-Hématologique and.
8
INSERM U1209, CNRS UMR 5309, Faculté de Médecine, Université Grenoble Alpes, Institut Albert Bonniot, Grenoble, France; Labortoire de Génétique Onco-Hématologique and.
9
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;
10
Departement de Dermatologie, Centre Hospitalier et Universitaire de Grenoble-Alpes, Grenoble, France;
11
Department of Community Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan;
12
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;
13
INSERM U1209, CNRS UMR 5309, Faculté de Médecine, Université Grenoble Alpes, Institut Albert Bonniot, Grenoble, France; Laboratoire d'Immunologie and.
14
Departement d'Hématologie Clinique, Centre Hospitalier et Universitaire de Grenoble-Alpes, Grenoble, France;
15
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;
16
Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands;
17
Department of Medicine, Perugia University, Perugia, Italy;
18
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;
19
Unité Fonctionnelle de Cytogénétique Hématologique, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; and.
20
Laboratoire d'Hématologie, Pôle de biologie, Centre Hospitalier et Universitaire de Toulouse, Toulouse, France.

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.

PMID:
27060168
PMCID:
PMC5043425
DOI:
10.1182/blood-2015-09-671040
[Indexed for MEDLINE]
Free PMC Article

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