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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
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 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. (
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Submitted on : Tuesday, November 13, 2018 - 10:58:27 AM
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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, American Society of Hematology, 2016, 127 (24), pp.3040 - 3053. ⟨10.1182/blood-2015-09-671040⟩. ⟨hal-01920364⟩



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