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

Abstract

Key Points• NR3C1 haploinsufficiency is found in patients with a plasmacytoid dendritic cell neoplasm characterized by very poor clinical outcome.• Overexpression of lincRNA3q is a consistent feature of malignant cells in these patients and can be abrogated by BET protein inhibition.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-of-EZH2 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 of lincRNA-3q was a consistent feature of malignant 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. (Blood. 2016;127(24):3040-3053)

Whole‐genome analysis uncovers recurrent IKZF1 inactivation and aberrant cell adhesion in blastic plasmacytoid dendritic cell neoplasm

“…We found that genes silenced by PRC2 (EZH2) were the most overrepresented in the group of up‐regulated genes in BPDCN. This agrees with a previous report of a loss‐of‐EZH2 expression signature in tumor cells from patients with highly aggressive BPDCN . Remarkably, it has been established that IKZF1, which predominantly acts as a transcriptional repressor, silences genes in erythroid and T‐cell precursors by recruiting PRC2 to target sites .…”

“…BPDCN, blastic plasmacytoid dendritic cell neoplasm; CPC, chromosomal passenger complex; NDC80, NDC80 kinetochore complex [Color figure can be viewed at wileyonlinelibrary.com] with a previous report of a loss-of-EZH2 expression signature in tumor cells from patients with highly aggressive BPDCN. 54 Remarkably, it has been established that IKZF1, which predominantly acts as a transcriptional repressor, silences genes in erythroid and T-cell precursors by recruiting PRC2 to target sites. 55,56 Thus, up-regulation of genes silenced by PRC2 in BPDCN might result from shortage of functional IKZF1 molecules, which in turn, would hinder PRC2 recruitment to target sites.…”

BET Family Protein BRD4: An Emerging Actor in NFκB Signaling in Inflammation and Cancer

“…Numerous studies indicate that BET inhibition is an attractive therapeutic strategy in hematological and solid cancers. Single or dual agent therapy is showing promise pre-clinically [ 1 , 3 , 6 , 31 , 32 ]. Inhibitors are mostly small molecule inhibitors that are thought to mediate anti-cancer activity through the interruption of interactions between BET proteins and acetylated lysine in histones at promoters and enhancers.…”

Blastic plasmacytoid dendritic cell neoplasm: genomics mark epigenetic dysregulation as a primary therapeutic target

“…7 The pathobiology of BPDCN is poorly understood and the number of reports exploring its molecular features is still limited. 8–21 Recent advances in the understanding of the BPDCN molecular landscape have paved the way for novel treatment approaches based on the inhibition of the BCL2 protein, 22 the activation of the cholesterol efflux, 23 the repression of the Bromodomain-containing protein 4 (BRD4), 24 and binding to the interleukin-3 receptor (IL3R). 25 All these potential therapeutic options (which are worthy of further evaluation) have mainly emerged from the analysis of the BPDCN transcriptome or from its antigenic repertoire.…”