7 research outputs found
miR-581-Related Single Nucleotide Polymorphism, rs2641726, Located in MUC4 Gene, is Associated with Gastric Cancer Incidence
Haploinsufficiency for NR3C1, the gene encoding the glucocorticoid receptor, in blastic plasmacytoid dendritic cell neoplasms
International audienceBlastic 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.