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

Maria Rosaria Sapienza, Francesco Abate, Federica Melle, Stefania Orecchioni, Fabio Fuligni, Maryam Etebari, Valentina Tabanelli, Maria Antonella Laginestra, Alessandro Pileri, Giovanna Motta, Maura Rossi, Claudio Agostinelli, Elena Sabattini, Nicola Pimpinelli, Mauro Truni, Brunangelo Falini, Lorenzo Cerroni, Giovanna Talarico, Rossana Piccioni, Stefano AmenteValentina Indio, Giuseppe Tarantino, Francesco Brundu, Marco Paulli, Emilio Berti, Fabio Facchetti, Gaetano Ivan Dellino, Francesco Bertolini, Claudio Tripodo, Raul Rabadan, Stefano A Pileri

Research output: Contribution to journalArticlepeer-review


Blastic Plasmacytoid Dendritic Cell Neoplasm is a rare and aggressive hematological malignancy currently lacking an effective therapy. To possibly identify genetic alterations useful for a new treatment design, we analyzed by whole-exome sequencing fourteen Blastic Plasmacytoid Dendritic Cell Neoplasm patients and the patient-derived CAL-1 cell line. The functional enrichment analysis of mutational data reported the epigenetic regulatory program as the most significantly undermined (P<.0001). In particular, twenty-five epigenetic-modifiers were found mutated (e.g., ASXL1, TET2, SUZ12, ARID1A, PHF2, CHD8); ASXL1 was the most frequently affected (28.6% of cases). To evaluate the impact of the identified epigenetic mutations at the gene-expression and Histone H3 lysine 27 trimethylation/acetylation levels, we performed additional RNA and Pathology tissue-chromatin immunoprecipitation sequencing experiments; the patients displayed enrichment in gene-signatures regulated by methylation and modifiable by Decitabine administration, shared common H3K27-acetylated regions and featured a set of cell-cycle genes aberrantly up-regulated and marked by promoter acetylation. Collectively, the integration of sequencing data showed the potential of a therapy based on epigenetic agents. Through the adoption of a preclinical Blastic Plasmacytoid Dendritic Cell Neoplasm mouse model, established by the CAL-1 cell line xenografting, we demonstrated the efficacy of the combination of the epigenetic drugs 5'-Azacytidine and Decitabine in controlling the disease progression in vivo.

Original languageEnglish
Publication statusE-pub ahead of print - Oct 31 2018


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