Emadali Anouk, Hoghoughi Neda, Duley Samuel, Hajmirza Azadeh, Verhoeyen Els, Cosset Francois-Loic, Bertrand Philippe, Roumier Christophe, Roggy Anne, Suchaud-Martin Céline, Chauvet Martine, Bertrand Sarah, Hamaidia Sieme, Rousseaux Sophie, Josserand Véronique, Charles Julie, Templier Isabelle, Maeda Takahiro, Bruder-Costa Juliana, Chaperot Laurence, Plumas Joel, Jacob Marie-Christine, Bonnefoix Thierry, Park Sophie, Gressin Remy, Tensen Cornelis P, Mecucci Cristina, Macintyre Elizabeth, Leroux Dominique, Brambilla Elisabeth, Nguyen-Khac Florence, Luquet Isabelle, Penther Dominique, Bastard Christian, Jardin Fabrice, Lefebvre Christine, Garnache Francine, Callanan Mary B
INSERM U1209, CNRS UMR 5309, Faculté de Médecine, Université Grenoble Alpes, Institut Albert Bonniot, Grenoble, France;
International Center for Infectiology Research, Université de Lyon 1, Lyon, France; INSERM U1111, CNRS UMR 5308, Ecole Normale Supérieure de Lyon, Lyon, France; INSERM U1065, Centre Méditerranéen de Médecine Moléculaire, Nice, France;
Blood. 2016 Jun 16;127(24):3040-53. doi: 10.1182/blood-2015-09-671040. Epub 2016 Apr 8.
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 = .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.
母细胞样浆细胞样树突状细胞肿瘤（BPDCN）是一种罕见且侵袭性很强的白血病，目前对其疾病机制和有效治疗方法的了解尚缺。仅发现了少数复发性基因突变，且没有一个是BPDCN特有的。在本研究中，通过对一名呈现平衡t(3;5)(q21;q31)的索引病例进行分子克隆，并对另外46例病例进行分子细胞遗传学分析，我们在47例BPDCN患者中的13例（28%）中发现了编码糖皮质激素受体（GCR）的NR3C1（5q31）单等位基因缺失。对36例BPDCN病例（包括10例NR3C1缺失病例）进行靶向深度测序，未发现NR3C1点突变或插入缺失。NR3C1单倍体不足定义了一个BPDCN亚组，其GCR表达降低，总体生存率极差（P = 0.0006）。与GCR在肿瘤抑制中的作用一致，功能分析与基因表达谱分析确定皮质抗性和EZH2功能丧失是BPDCN中NR3C1缺失的主要下游后果。随后，对t(3;5)(q21;q31)进行更详细的分析发现，NR3C1与一个长链非编码RNA（lncRNA）基因（lincRNA - 3q）融合，该基因编码一种新型的、核内的、参与白血病干细胞程序调控和G1/S期转换的非编码RNA，通过E2F发挥作用。lincRNA - 3q的过表达是恶性细胞的一个一致特征，并且可以通过抑制溴结构域和额外末端结构域（BET）蛋白来消除。综上所述，这项研究表明NR3C1是BPDCN一个亚组中的单倍体不足肿瘤抑制因子，并确定BET抑制至少部分通过lncRNA阻断发挥作用，是BPDCN的一种新的治疗选择。
