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.

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

Sapienza, Maria Rosaria;Melle, Federica;Fuligni, Fabio;Etebari, Maryam;Tabanelli, Valentina;Laginestra, Maria Antonella;Pileri, Alessandro;Motta, Giovanna;Rossi, Maura;Agostinelli, Claudio;Sabattini, Elena;Indio, Valentina;Tarantino, Giuseppe;Pileri, Stefano A
2019

Abstract

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.
HAEMATOLOGICA
Sapienza, Maria Rosaria; Abate, Francesco; Melle, Federica; Orecchioni, Stefania; Fuligni, Fabio; Etebari, Maryam; Tabanelli, Valentina; Laginestra, Maria Antonella; Pileri, Alessandro; Motta, Giovanna; Rossi, Maura; Agostinelli, Claudio; Sabattini, Elena; Pimpinelli, Nicola; Truni, Mauro; Falini, Brunangelo; Cerroni, Lorenzo; Talarico, Giovanna; Piccioni, Rossana; Amente, Stefano; Indio, Valentina; Tarantino, Giuseppe; Brundu, Francesco; Paulli, Marco; Berti, Emilio; Facchetti, Fabio; Dellino, Gaetano Ivan; Bertolini, Francesco; Tripodo, Claudio; Rabadan, Raul; Pileri, Stefano A
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11585/649041
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