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Haematologica. 2019 Apr;104(4):729-737. doi: 10.3324/haematol.2018.202093. Epub 2018 Oct 31.

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

Author information

1
Hematopathology Unit, Department of Experimental, Diagnostic, and Specialty Medicine, S. Orsola-Malpighi Hospital, University of Bologna, Italy mariarosaria.sapienza@gmail.com.
2
Department of Systems Biology, Columbia University College of Physicians and Surgeons, New York, NY, USA.
3
Department of Biomedical Informatics, Columbia University College of Physicians and Surgeons, New York, NY, USA.
4
Division of Haematopathology, IEO European Institute of Oncology IRCCS, Milan, Italy.
5
Laboratory of Hematology-Oncology, IEO European Institute of Oncology IRCCS, Milan, Italy.
6
Department of Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
7
Hematopathology Unit, Department of Experimental, Diagnostic, and Specialty Medicine, S. Orsola-Malpighi Hospital, University of Bologna, Italy.
8
Dermatology Unit, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Italy.
9
Division of Dermatology, Department of Surgery and Translational Medicine, University of Florence, Italy.
10
Pathological Anatomy Histology & Cytogenetics, Niguarda Cancer Center, Niguarda-Ca' Granda Hospital, Milan, Italy.
11
Institute of Hematology and Center for Hemato-Oncology Research (CREO), University and Hospital of Perugia, Italy.
12
Universitätsklinik für Dermatologie und Venerologie, LKH-Universitatsklinikum Graz, Austria.
13
Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
14
Department of Molecular Medicine and Medical Biotechnologies, University of Naples 'Federico II', Italy.
15
"Giorgio Prodi" Cancer Research Center, University of Bologna, Italy.
16
Unit of Anatomic Pathology, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS San Matteo Policlinic, Pavia, Italy.
17
Department of Dermatology, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinic and Milan University, Milan, Italy.
18
Pathology Section, Department of Molecular and Translational Medicine, University of Brescia, Italy.
19
Department of Oncology and Hemato-Oncology, University of Milan, Italy.
20
Tumor Immunology Unit, Department of Health Science, Human Pathology Section, University of Palermo School of Medicine, Italy.

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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