Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz

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SHR Neuro Krebs Kardio Lipid

Sapienza, MR; Abate, F; Melle, F; Orecchioni, S; Fuligni, F; Etebari, M; Tabanelli, V; Laginestra, MA; 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, GI; Bertolini, F; Tripodo, C; Rabadan, R; Pileri, SA.
Blastic plasmacytoid dendritic cell neoplasm: genomics mark epigenetic dysregulation as a primary therapeutic target
HAEMATOLOGICA. 2019; 104(4): 729-737.
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Autor/innen der Med Uni Graz:
Cerroni Lorenzo
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Abstract:
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy for which there is still no effective 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.

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