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

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

Blood. 2016 Apr 8;

Authors: Emadali A, Hoghoughi N, Duley S, Hajmirza A, Verhoeyen E, Cosset FL, Bertrand P, Roumier C, Roggy A, Suchaud-Martin C, Chauvet M, Bertrand S, Hamaidia S, Rousseaux S, Josserand V, Charles J, Templier I, Maeda T, Bruder-Costa J, Chaperot L, Plumas J, Jacob MC, Bonnefoix T, Park S, Gressin R, Tensen CP, Mecucci C, Macintyre E, Leroux D, Brambilla E, Nguyen-Khac F, Luquet I, Penther D, Bastard C, Jardin F, Lefebvre C, Garnache F, Callanan M

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 are 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 ofNR3C1(5q31), encoding the glucocorticoid receptor (GCR), in 13 of 47 (28%) BPDCN patients. Targeted deep sequencing in 36 BPDCN cases, including 10 withNR3C1deletion, did not revealNR3C1point mutations or in/dels. Haploinsufficiency forNR3C1defined a subset of BPDCN with lowered GCR expression and extremely poor overall survival (P = 0.0006). Consistent with a role for GCR in tumor suppression, functional analyses coupled with gene expression profiling (GEP), identified cortico-resistance and loss-of-EZH2 function to be major downstream consequences ofNR3C1deletion in BPDCN. Subsequently, more detailed analyses of the t(3;5)(q21;q31) revealed fusion ofNR3C1to a lncRNA gene (lincRNA-3q) that encodes a novel, nuclear, non-coding RNA involved in the regulation of leukemia stem cell programmes and G1/S transition, via E2F. Overexpression oflincRNA-3qwas a consistent feature of malignant cells and could be abrogated by BET protein (bromo and extra-terminal domain) inhibition. Taken together, this work points toNR3C1as 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.

PMID: 27060168 [PubMed - as supplied by publisher]

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