Page 101 - 2019_04-Haematologica-web

Myeloid Neoplasms
Blastic plasmacytoid dendritic cell neoplasm: genomics mark epigenetic dysregulation as a primary therapeutic target
Ferrata Storti Foundation
Haematologica 2019 Volume 104(4):729-737
Maria Rosaria Sapienza,1* Francesco Abate,2,3* Federica Melle,4
Stefania Orecchioni,5 Fabio Fuligni,6 Maryam Etebari,1 Valentina Tabanelli,4 Maria Antonella Laginestra,1 Alessandro Pileri,7,8 Giovanna Motta,4
Maura Rossi,1 Claudio Agostinelli,1 Elena Sabattini,1 Nicola Pimpinelli,8 Mauro Truni,9 Brunangelo Falini,10 Lorenzo Cerroni,11 Giovanna Talarico,5 Rossana Piccioni,12 Stefano Amente,13 Valentina Indio,14
Giuseppe Tarantino,14 Francesco Brundu,2 Marco Paulli,15 Emilio Berti,16 Fabio Facchetti,17 Gaetano Ivan Dellino,12,18 Francesco Bertolini,5
Claudio Tripodo,19* Raul Rabadan2,3* and Stefano A. Pileri4ǂ*
1Hematopathology Unit, Department of Experimental, Diagnostic, and Specialty Medicine, S. Orsola-Malpighi Hospital, University of Bologna, Italy; 2Department of Systems Biology, Columbia University College of Physicians and Surgeons, New York,
NY, USA; 3Department of Biomedical Informatics, Columbia University College of Physicians and Surgeons, New York, NY, USA; 4Division of Haematopathology, European Institute of Oncology, Milan, Italy; 5Laboratory of Hematology-Oncology, European Institute of Oncology, Milan, Italy; 6Department of Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada: 7Dermatology Unit, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Italy; 8Division of Dermatology, Department of Surgery and Translational Medicine, University of Florence, Italy; 9Pathological Anatomy Histology & Cytogenetics, Niguarda Cancer Center, Niguarda-Ca' Granda Hospital, Milan, Italy; 10Institute of Hematology and Center for Hemato-Oncology Research (CREO), University and Hospital of Perugia, Italy; 11Universitätsklinik für Dermatologie und Venerologie, LKH-Universitatsklinikum Graz, Austria; 12Department of Experimental Oncology, European Institute of Oncology, Milan, Italy; 13Department of Molecular Medicine and Medical Biotechnologies, University of Naples ‘Federico II’, Italy; 14"Giorgio Prodi" Cancer Research Center, University of Bologna, Italy; 15Unit of Anatomic Pathology, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS San Matteo Policlinic, Pavia, Italy; 16Department of Dermatology, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinic and Milan University, Milan, Italy; 17Pathology Section, Department of Molecular and Translational Medicine, University of Brescia, Italy; 18Department of Oncology and Hemato-Oncology, University of Milan, Italy and 19Tumor Immunology Unit, Department of Health Science, Human Pathology Section, University of Palermo School of Medicine, Italy ǂ
*MRS, FA, CT, RR and SAP contributed equally to this work. Alma Mater Professor, Bologna University
ABSTRACT
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy for which there is still no effec- tive 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 regulato- ry program to be the most significantly undermined (P<0.0001). In par- ticular, twenty-five epigenetic modifiers were found mutated (e.g. ASXL1, TET2, SUZ12, ARID1A, PHF2, CHD8); ASXL1 was the most fre- quently affected (28.6% of cases). To evaluate the impact of the identi- fied epigenetic mutations at the gene-expression and Histone H3 lysine 27 trimethylation/acetylation levels, we performed additional RNA and pathology tissue-chromatin immunoprecipitation sequencing experi- ments. 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 preclin- ical 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.
Correspondence:
MARIA ROSARIA SAPIENZA
mariarosaria.sapienza@gmail.com
Received: July 16, 2018. Accepted: October 30, 2018. Pre-published: October 31, 2018.
doi:10.3324/haematol.2018.202093
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/4/729
©2019 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
haematologica | 2019; 104(4)
729
ARTICLE