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

A. Emadali (1) , N. Hoghoughi (1) , S. Duley (1) , A. Hajmirza (1) , Els Verhoeyen (2, 3) , Cosset François-Loïc (2) , Pierre Bertrand (4) , C. Roumier (5) , A. Roggy (6) , C. Suchaud-Martin (7) , M. Chauvet (7, 1) , S. Bertrand (1) , S. Hamaidia (1, 7) , S. Rousseaux (1) , V. Josserand (1) , Jérôme Charles (1, 7) , I. Templier (7) , T. Maeda (8) , J. Bruder-Costa (1, 9) , L. Chaperot (1, 9) , J. Plumas (1, 9) , M. Jacob (1, 7) , T. Bonnefoix (1) , S. Park (7) , R. Gressin (1, 7) , C. Tensen (10) , C. Mecucci (11) , E. Macintyre (12) , D. Leroux (1, 7) , Elizabeth Brambilla (1) , F. Nguyen-Khac (13) , I. Luquet (14) , D. Penther (4) , C. Bastard (4) , F. Jardin (4) , C. Lefebvre (1, 7) , F. Garnache (6) , M. Callanan (1, 7)

1 IAB - Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble)
2 EVIR - Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy
3 C3M - Centre méditerranéen de médecine moléculaire
4 GPL - Groupe d'étude des proliférations lymphoïdes
5 Service d'Hématologie Cellulaire [Lille]
6 EFS BFC - Etablissement français du sang [Bourgogne-Franche-Comté]
7 CHU de Grenoble-Alpes
8 Graduate School of Biomedical Sciences [Nagasaki University, Japan]
9 EFS - Etablissement français du sang - Auvergne-Rhône-Alpes
10 LUMC - Leiden University Medical Center
11 UNIPG - Università degli Studi di Perugia = University of Perugia
12 INEM - UM 111 (UMR 8253 / U1151) - Institut Necker Enfants-Malades
13 CHU Pitié-Salpêtrière [AP-HP]
14 Service Hématologie - IUCT-Oncopole [CHU Toulouse]

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 5 .0006). Consistent with a role for GCR in tumor suppression, functional analyses 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 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 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 and identifies BET inhibition, acting at least partially via lncRNA blockade, as a novel treatment option in BPDCN. (

Domaines: Immunologie; Virologie; Bactériologie

A. Emadali, N. Hoghoughi, S. Duley, A. Hajmirza, Els Verhoeyen, et al.. Haploinsufficiency for NR3C1, the gene encoding the glucocorticoid receptor, in blastic plasmacytoid dendritic cell neoplasms. Blood, 2016, 127 (24), pp.3040 - 3053. ⟨10.1182/blood-2015-09-671040⟩. ⟨hal-01920364⟩