%0 Journal Article %T Haploinsufficiency for NR3C1, the gene encoding the glucocorticoid receptor, in blastic plasmacytoid dendritic cell neoplasms %+ Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB) %+ Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (EVIR) %+ Centre méditerranéen de médecine moléculaire (C3M) %+ Groupe d'étude des proliférations lymphoïdes (GPL) %+ Service d'Hématologie Cellulaire [Lille] %+ Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]) %+ CHU de Grenoble-Alpes %+ Graduate School of Biomedical Sciences [Nagasaki University, Japan] %+ 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)) %+ CHU Pitié-Salpêtrière [AP-HP] %+ Laboratoire d'Hématologie [Purpan] %A Emadali, A. %A Hoghoughi, N. %A Duley, S. %A Hajmirza, A. %A Verhoeyen, Els %A François-Loïc, Cosset %A Bertrand, Pierre %A Roumier, C. %A Roggy, A. %A Suchaud-Martin, C. %A Chauvet, M. %A Bertrand, S. %A Hamaidia, S. %A Rousseaux, S. %A Josserand, V. %A Charles, Jérôme %A Templier, I. %A Maeda, T. %A Bruder-Costa, J. %A Chaperot, L. %A Plumas, J. %A Jacob, M. %A Bonnefoix, T. %A Park, S. %A Gressin, R. %A Tensen, C. %A Mecucci, C. %A Macintyre, E. %A Leroux, D. %A Brambilla, Elizabeth %A Nguyen-Khac, F. %A Luquet, I. %A Penther, D. %A Bastard, C. %A Jardin, F. %A Lefebvre, C. %A Garnache, F. %A Callanan, M. %< avec comité de lecture %@ 0006-4971 %J Blood %I American Society of Hematology %V 127 %N 24 %P 3040 - 3053 %8 2016-06-16 %D 2016 %R 10.1182/blood-2015-09-671040 %Z Life Sciences [q-bio]/Immunology %Z Life Sciences [q-bio]/Microbiology and Parasitology/Virology %Z Life Sciences [q-bio]/Microbiology and Parasitology/BacteriologyJournal articles %X 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. ( %G English %L hal-01920364 %U https://univ-lyon1.hal.science/hal-01920364 %~ ENS-LYON %~ UNICE %~ UNIV-PARIS5 %~ UGA %~ CNRS %~ UNIV-LYON1 %~ APHP %~ COMUE-NORMANDIE %~ USPC %~ UNIV-COTEDAZUR %~ UNIROUEN %~ CIRI %~ SORBONNE-UNIVERSITE %~ SU-INF-2018 %~ SU-MEDECINE %~ SU-MED %~ GPMCND %~ UDL %~ UNIV-LYON %~ UNIV-PARIS %~ UP-SANTE %~ UGA-COMUE %~ SU-TI %~ CIRI-F-L-COSSET-EVIR %~ ALLIANCE-SU %~ C3M %~ TEST3-HALCNRS