Published June 16, 2016
| Version v1
Journal article
Haploinsufficiency for NR3C1, the gene encoding the glucocorticoid receptor, in blastic plasmacytoid dendritic cell neoplasms
Creators
- Emadali, A.
- Hoghoughi, N.
- Duley, S.
- Hajmirza, A.
- Verhoeyen, Els
- François-Loïc, Cosset
- Bertrand, Pierre
- Roumier, C.
- Roggy, A.
- Suchaud-Martin, C.
- Chauvet, M.
- Bertrand, S.
- Hamaidia, S.
- Rousseaux, S.
- Josserand, V.
- Charles, Jérôme
- Templier, I.
- Maeda, T.
- Bruder-Costa, J.
- Chaperot, L.
- Plumas, J.
- Jacob, M.
- Bonnefoix, T.
- Park, S.
- Gressin, R.
- Tensen, C.
- Mecucci, C.
- Macintyre, E.
- Leroux, D.
- Brambilla, Elizabeth
- Nguyen-Khac, F.
- Luquet, I.
- Penther, D.
- Bastard, C.
- Jardin, F.
- Lefebvre, C.
- Garnache, F.
- Callanan, M.
Contributors
Others:
- Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB) ; Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])
- Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (EVIR) ; Centre International de Recherche en Infectiologie - UMR (CIRI) ; École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL) ; Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL) ; Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
- Centre méditerranéen de médecine moléculaire (C3M) ; Université Nice Sophia Antipolis (1965 - 2019) (UNS) ; COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)
- Groupe d'étude des proliférations lymphoïdes (GPL) ; Université de Rouen Normandie (UNIROUEN) ; Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)
- Service d'Hématologie Cellulaire [Lille] ; Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)
- Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])
- CHU de Grenoble-Alpes
- Graduate School of Biomedical Sciences [Nagasaki University, Japan] ; Nagasaki University
- Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)
- Leiden University Medical Center (LUMC)
- Università degli Studi di Perugia = University of Perugia (UNIPG)
- Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)) ; Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
- CHU Pitié-Salpêtrière [AP-HP] ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
- Laboratoire d'Hématologie [Purpan] ; CHU Toulouse [Toulouse]
Description
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and highly aggressiveleukemia for which knowledge on disease mechanisms and effective therapies are currentlylacking. Only a handful of recurring genetic mutations have been identified and none isspecific to BPDCN. In this study, through molecular cloning in an index case that presenteda balanced t(3;5)(q21;q31) and molecular cytogenetic analyses in a further 46 cases, weidentify monoallelic deletion of NR3C1 (5q31), encoding the glucocorticoid receptor (GCR),in 13 of 47 (28%) BPDCN patients. Targeted deep sequencing in 36 BPDCN cases, including10 with NR3C1 deletion, did not reveal NR3C1 point mutations or indels. Haploinsufficiencyfor NR3C1 defined a subset of BPDCN with lowered GCR expression and extremely pooroverall survival (P 5 .0006). Consistent with a role for GCR in tumor suppression, functionalanalyses coupled with gene expression profiling identified corticoresistance and loss-ofEZH2 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 along noncoding RNA (lncRNA) gene (lincRNA-3q) that encodes a novel, nuclear, noncodingRNA involved in the regulation of leukemia stem cell programs and G1/S transition, via E2F.Overexpression oflincRNA-3qwas a consistent feature ofmalignant 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 andidentifies BET inhibition, acting at least partially via lncRNA blockade, as a novel treatment option in BPDCN. (
Abstract
International audienceAdditional details
Identifiers
- URL
- https://hal-univ-lyon1.archives-ouvertes.fr/hal-01920364
- URN
- urn:oai:HAL:hal-01920364v1
Origin repository
- Origin repository
- UNICA