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 CIRI-EVIR - Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy [CIRI]
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]
2 CIRI-EVIR - Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy [CIRI]
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]
Els Verhoeyen
- Fonction : Auteur
- PersonId : 1100507
- ORCID : 0000-0001-9224-5491
- IdRef : 159656028
Cosset François-Loïc
- Fonction : Auteur
- PersonId : 746240
- IdHAL : francois-loic-cosset
- ORCID : 0000-0001-8842-3726
- IdRef : 11115104X
L. Chaperot
- Fonction : Auteur
- PersonId : 1312440
- ORCID : 0000-0002-1479-9410
- IdRef : 139764496
J. Plumas
- Fonction : Auteur
- PersonId : 1312441
- ORCID : 0000-0002-5005-4301
- IdRef : 077252683
Résumé
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. (