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

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

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)


Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy for which there is still no effective B therapy. In order to identify genetic alterations useful for a new treatment design, we used whole-exome sequencing to analyze 14 BPDCN patients and the patient-derived CAL-1 cell line. The functional enrichment analysis of mutational data reported the epigenetic regulatory program to be the most significantly undermined (P<0.0001). 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 had 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 BPDCN mouse model, established by CAL-1 cell line xenografting, we demonstrated the efficacy of the combination of the epigenetic drugs 5’-azacytidine and decitabine in controlling disease progression in vivo.
Original languageEnglish
Pages (from-to)729-737
Number of pages9
Publication statusPublished - 2019

All Science Journal Classification (ASJC) codes

  • Hematology

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