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

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

Edité par CCSD ; American Society of Hematology -

International audience. Blastic 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. (

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