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

Articolo
Data di Pubblicazione:
2019
Abstract:
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.
Tipologia CRIS:
1.1 Articolo in rivista
Keywords:
Aged; Animals; Azacitidine; Cell Line, Tumor; Decitabine; Epigenesis, Genetic; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Mice, Inbred NOD; Mice, SCID; Middle Aged; Xenograft Model Antitumor Assays; Hematologic Neoplasms; Myeloproliferative Disorders; Neoplasm Proteins; Skin Neoplasms
Elenco autori:
Sapienza, M. R.; Abate, F.; Melle, F.; Orecchioni, S.; Fuligni, F.; Etebari, M.; Tabanelli, V.; Laginestra, M. A.; Pileri, A.; Motta, G.; Rossi, M.; Agostinelli, C.; Sabattini, E.; Pimpinelli, N.; Truni, M.; Falini, B.; Cerroni, L.; Talarico, G.; Piccioni, R.; Amente, S.; Indio, V.; Tarantino, G.; Brundu, F.; Paulli, M.; Berti, E.; Facchetti, F.; Dellino, G. I.; Bertolini, F.; Tripodo, C.; Rabadan, R.; Pileri, S. A.
Autori di Ateneo:
PAULLI MARCO
Link alla scheda completa:
https://iris.unipv.it/handle/11571/1373743
Pubblicato in:
HAEMATOLOGICA
Journal
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