TY - JOUR
T1 - Blastic plasmacytoid dendritic cell neoplasm
T2 - genomics mark epigenetic dysregulation as a primary therapeutic target
AU - Sapienza, Maria Rosaria
AU - Abate, Francesco
AU - Melle, Federica
AU - Orecchioni, Stefania
AU - Fuligni, Fabio
AU - Etebari, Maryam
AU - Tabanelli, Valentina
AU - Laginestra, Maria Antonella
AU - Pileri, Alessandro
AU - Motta, Giovanna
AU - Rossi, Maura
AU - Agostinelli, Claudio
AU - Sabattini, Elena
AU - Pimpinelli, Nicola
AU - Truni, Mauro
AU - Falini, Brunangelo
AU - Cerroni, Lorenzo
AU - Talarico, Giovanna
AU - Piccioni, Rossana
AU - Amente, Stefano
AU - Indio, Valentina
AU - Tarantino, Giuseppe
AU - Brundu, Francesco
AU - Paulli, Marco
AU - Berti, Emilio
AU - Facchetti, Fabio
AU - Dellino, Gaetano Ivan
AU - Bertolini, Francesco
AU - Tripodo, Claudio
AU - Rabadan, Raul
AU - Pileri, Stefano A
N1 - Copyright © 2018, Ferrata Storti Foundation.
PY - 2018/10/31
Y1 - 2018/10/31
N2 - 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.
AB - 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.
U2 - 10.3324/haematol.2018.202093
DO - 10.3324/haematol.2018.202093
M3 - Article
C2 - 30381297
JO - Haematologica
JF - Haematologica
SN - 0390-6078
ER -