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

M.R. Sapienza, F. Abate, F. Melle, S. Orecchioni, F. Fuligni, M. Etebari, V. Tabanelli, M.A. Laginestra, A. Pileri, G. Motta, M. Rossi, C. Agostinelli, E. Sabattini, N. Pimpinelli, M. Truni, B. Falini, L. Cerroni, G. Talarico, R. Piccioni, S. AmenteV. Indio, G. Tarantino, F. Brundu, M. Paulli, E. Berti, F. Facchetti, G.I. Dellino, F. Bertolini, C. Tripodo, R. Rabadan, S.A. Pileri

Research output: Contribution to journalArticle

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
Original languageEnglish
Pages (from-to)729-737
Number of pages9
JournalHaematologica
Volume104
Issue number4
DOIs
Publication statusPublished - 2019

Fingerprint

Genomics
Epigenomics
Dendritic Cells
Exome
Hematologic Neoplasms
Neoplasms
Cell Line
Therapeutics

Keywords

  • azacitidine
  • decitabine
  • romidepsin
  • transcriptome
  • adult
  • animal experiment
  • animal model
  • animal tissue
  • Article
  • CAL-1 [Human melanoma] cell line
  • chromatin immunoprecipitation
  • clinical article
  • controlled study
  • dendritic cell sarcoma
  • epigenetics
  • female
  • gene mutation
  • hematopoietic stem cell transplantation
  • histone methylation
  • human
  • immune dysregulation
  • immunohistochemistry
  • male
  • middle aged
  • mouse
  • nonhuman
  • plasmacytoid dendritic cell
  • protein expression
  • RNA sequence
  • Sanger sequencing
  • single nucleotide polymorphism
  • somatic mutation
  • upregulation
  • whole exome sequencing

Cite this

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

In: Haematologica, Vol. 104, No. 4, 2019, p. 729-737.

Research output: Contribution to journalArticle

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 2019, 'Blastic plasmacytoid dendritic cell neoplasm: Genomics mark epigenetic dysregulation as a primary therapeutic target', Haematologica, vol. 104, no. 4, pp. 729-737. https://doi.org/10.3324/haematol.2018.202093
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. / Blastic plasmacytoid dendritic cell neoplasm: Genomics mark epigenetic dysregulation as a primary therapeutic target. In: Haematologica. 2019 ; Vol. 104, No. 4. pp. 729-737.
@article{c0ad4d3e84684ec3a0cf581be36669c5,
title = "Blastic plasmacytoid dendritic cell neoplasm: Genomics mark epigenetic dysregulation as a primary therapeutic target",
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",
keywords = "azacitidine, decitabine, romidepsin, transcriptome, adult, animal experiment, animal model, animal tissue, Article, CAL-1 [Human melanoma] cell line, chromatin immunoprecipitation, clinical article, controlled study, dendritic cell sarcoma, epigenetics, female, gene mutation, hematopoietic stem cell transplantation, histone methylation, human, immune dysregulation, immunohistochemistry, male, middle aged, mouse, nonhuman, plasmacytoid dendritic cell, protein expression, RNA sequence, Sanger sequencing, single nucleotide polymorphism, somatic mutation, upregulation, whole exome sequencing",
author = "M.R. Sapienza and F. Abate and F. Melle and S. Orecchioni and F. Fuligni and M. Etebari and V. Tabanelli and M.A. Laginestra and A. Pileri and G. Motta and M. Rossi and C. Agostinelli and E. Sabattini and N. Pimpinelli and M. Truni and B. Falini and L. Cerroni and G. Talarico and R. Piccioni and S. Amente and V. Indio and G. Tarantino and F. Brundu and M. Paulli and E. Berti and F. Facchetti and G.I. Dellino and F. Bertolini and C. Tripodo and R. Rabadan and S.A. Pileri",
note = "Cited By :3 Export Date: 10 October 2019 CODEN: HAEMA Correspondence Address: Sapienza, M.R.; Hematopathology Unit, Department of Experimental, Diagnostic, and Specialty Medicine, S. Orsola-Malpighi Hospital, University of BolognaItaly; email: mariarosaria.sapienza@gmail.com Chemicals/CAS: azacitidine, 320-67-2, 52934-49-3; decitabine, 2353-33-5; romidepsin, 128517-07-7 Funding details: Hospital for Sick Children Funding details: Universit{\`a} di Bologna Funding details: Universit{\`a} degli Studi di Brescia Funding details: Fondazione IRCCS Policlinico San Matteo Funding details: Universit{\`a} degli Studi di Napoli Federico II Funding details: Royal College of Physicians and Surgeons of Canada Funding details: Department of Surgery Funding details: Associazione Italiana per la Ricerca sul Cancro, 5x1000 10007, IG 15762 Funding text 1: 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; 11Universit{\"a}tsklinik f{\"u}r 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 and19Tumor Immunology Unit, Department of Health Science, Human Pathology Section, University of Palermo School of Medicine, Italy Funding text 2: The present work was supported by the AIRC grants IG 15762 and 5x1000 10007 “Genetics-driven targeted management of lymphoid malignancies” and the Grant “Innovative approaches to the diagnosis and pharmacogenetic-based therapies of primary hepatic tumours, peripheral B and T-cell lymphomas and lymphoblastic leukaemias” Strategic Programme 2010-2012 Regione Emilia Romagna - Universit{\`a} (all to SAP). References: Chaperot, L., Bendriss, N., Manches, O., Identification of a leukemic counterpart of the plasmacytoid dendritic cells (2001) Blood, 97 (10), pp. 3210-3217; Swerdlow, S.H., Campo, E., Hazzis, N.L., Facchetti F, Jones D, Petrella T. Blastic plasmacytoid dendritic cell neoplasm (2008) Swerdlow SH, pp. 145-147. , Campo E, Hazzis NL, et al., eds. WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press; Facchetti, F., Cigognetti, M., Fisogni, S., Rossi, G., Lonardi, S., Vermi, W., Neoplasms derived from plasmacytoid dendritic cells (2016) Mod Pathol, 29 (2), pp. 98-111; Garnache-Ottou, F., Feuillard, J., Ferrand, C., Extended diagnostic criteria for plasmacytoid dendritic cell leukaemia (2009) Br J Haematol, 145 (5), pp. 624-636; Pagano, L., Valentini, C.G., Pulsoni, A., Blastic plasmacytoid dendritic cell neoplasm with leukemic presentation: An Italian multicenter study (2013) Haematologica, 98 (2), pp. 239-246; Roos-Weil, D., Dietrich, S., Boumendil, A., Stem cell transplantation can provide durable disease control in blastic plasmacytoid dendritic cell neoplasm: A retrospective study from the European Group for Blood and Marrow Transplantation (2013) Blood, 121 (3), pp. 440-446; Pemmaraju, N., Blastic plasmacytoid dendritic cell neoplasm (2016) Clin Adv Hematol Oncol, 14 (4), pp. 220-222; Petrella, T., Dalac, S., Maynadie, M., CD4+ CD56+ cutaneous neoplasms: A distinct hematological entity? Groupe Francais d'Etude des Lymphomes Cutanes (GFELC) (1999) Am J Surg Pathol, 23 (2), pp. 137-146; Leroux, D., Mugneret, F., Callanan, M., CD4(+), CD56(+) DC2 acute leukemia is characterized by recurrent clonal chromosomal changes affecting 6 major targets: A study of 21 cases by the Groupe Francais de Cytogenetique Hematologique (2002) Blood, 99 (11), pp. 4154-4159; Reichard, K.K., Burks, E.J., Foucar, M.K., CD4(+) CD56(+) lineage-negative malignancies are rare tumors of plasmacytoid dendritic cells (2005) Am J Surg Pathol, 29 (10), pp. 1274-1283; Dijkman, R., van Doorn, R., Szuhai, K., Willemze, R., Vermeer, M.H., Tensen, C.P., Gene-expression profiling and array-based CGH classify CD4+CD56+ hematodermic neoplasm and cutaneous myelomonocytic leukemia as distinct disease entities (2007) Blood, 109 (4), pp. 1720-1727; Wiesner, T., Obenauf, A.C., Cota, C., Fried, I., Speicher, M.R., Cerroni, L., Alterations of the cell-cycle inhibitors p27(KIP1) and p16(INK4a) are frequent in blastic plasmacytoid dendritic cell neoplasms (2010) J Invest Dermatol, 130 (4), pp. 1152-1157; Agliano, A., Martin-Padura, I., Marighetti, P., Therapeutic effect of lenalidomide in a novel xenograft mouse model of human blastic NK cell lymphoma/blastic plasmacytoid dendritic cell neoplasm (2011) Clin Cancer Res, 17 (19), pp. 6163-6173; Jardin, F., Ruminy, P., Parmentier, F., TET2 and TP53 mutations are frequently observed in blastic plasmacytoid dendritic cell neoplasm (2011) Br J Haematol, 153 (3), pp. 413-416; Lucioni, M., Novara, F., Fiandrino, G., Twenty-one cases of blastic plasmacytoid dendritic cell neoplasm: Focus on biallelic locus 9p21.3 deletion (2011) Blood, 118 (17), pp. 4591-4594; Alayed, K., Patel, K.P., Konoplev, S., TET2 mutations, myelodysplastic features, and a distinct immunoprofile characterize blastic plasmacytoid dendritic cell neoplasm in the bone marrow (2013) Am J Hematol, 88 (12), pp. 1055-1061; Sapienza, M.R., Fuligni, F., Agostinelli, C., Molecular profiling of blastic plasmacytoid dendritic cell neoplasm reveals a unique pattern and suggests selective sensitivity to NF-kB pathway inhibition (2014) Leukemia, 28 (8), pp. 1606-1616; Philippe, L., Ceroi, A., Bole-Richard, E., Bortezomib as a new therapeutic approach for blastic plasmacytoid dendritic cell neoplasm (2017) Haematologica, 102 (11), pp. 1861-1868; Menezes, J., Acquadro, F., Wiseman, M., Exome sequencing reveals novel and recurrent mutations with clinical impact in blastic plasmacytoid dendritic cell neoplasm (2014) Leukemia, 28 (4), pp. 823-829; Stenzinger, A., Endris, V., Pfarr, N., Targeted ultra-deep sequencing reveals recurrent and mutually exclusive mutations of cancer genes in blastic plasmacytoid dendritic cell neoplasm (2014) Oncotarget, 5 (15), pp. 6404-6413; Emadali, A., Hoghoughi, N., Duley, S., Haploinsufficiency for NR3C1, the gene encoding the glucocorticoid receptor, in blastic plasmacytoid dendritic cell neoplasms (2016) Blood, 127 (24), pp. 3040-3053; Montero, J., Stephansky, J., Cai, T., Blastic Plasmacytoid Dendritic Cell Neoplasm Is Dependent on BCL2 and Sensitive to Venetoclax (2017) Cancer Discov, 7 (2), pp. 156-164; Ceroi, A., Masson, D., Roggy, A., LXR agonist treatment of blastic plasmacytoid dendritic cell neoplasm restores cholesterol efflux and triggers apoptosis (2016) Blood, 128 (23), pp. 2694-2707; Ceribelli, M., Hou, Z.E., Kelly, P.N., A Druggable TCF4-and BRD4-Dependent Transcriptional Network Sustains Malignancy in Blastic Plasmacytoid Dendritic Cell Neoplasm (2016) Cancer Cell, 30 (5), pp. 764-778; Angelot-Delettre, F., Roggy, A., Frankel, A.E., In vivo and in vitro sensitivity of blastic plasmacytoid dendritic cell neoplasm to SL-401, an interleukin-3 receptor targeted biologic agent (2015) Haematologica, 100 (2), pp. 223-230; Fanelli, M., Amatori, S., Barozzi, I., Pathology tissue-chromatin immunoprecipitation, coupled with high-throughput sequencing, allows the epigenetic profiling of patient samples (2010) Proc Natl Acad Sci U S A, 107 (50), pp. 21535-21540; Maeda, T., Murata, K., Fukushima, T., A novel plasmacytoid dendritic cell line, CAL-1, established from a patient with blastic natural killer cell lymphoma (2005) Int J Hematol, 81 (2), pp. 148-154; Ashburner, M., Ball, C.A., Blake, J.A., Gene ontology: Tool for the unification of biology. The Gene Ontology Consortium (2000) Nat Genet, 25 (1), pp. 25-29; Ward, A.F., Braun, B.S., Shannon, K.M., Targeting oncogenic Ras signaling in hematologic malignancies (2012) Blood, 120 (17), pp. 3397-3406; Guarini, A., Marinelli, M., Tavolaro, S., ATM gene alterations in chronic lymphocytic leukemia patients induce a distinct gene expression profile and predict disease progression (2012) Haematologica, 97 (1), pp. 47-55; Simon, M., Grandage, V.L., Linch, D.C., Khwaja, A., Constitutive activation of the Wnt/beta-catenin signalling pathway in acute myeloid leukaemia (2005) Oncogene, 24 (14), pp. 2410-2420; Kuo, Y.H., Zaidi, S.K., Gornostaeva, S., Komori, T., Stein, G.S., Castilla, L.H., Runx2 induces acute myeloid leukemia in cooperation with Cbfbeta-SMMHC in mice (2009) Blood, 113 (14), pp. 3323-3332; Togami, K., Madan, V., Li, J., Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) Harbors Frequent Splicesosome Mutations That Cause Aberrant RNA Splicing Affecting Genes Critical in pDC Differentiation and Function (2016) Blood, 128 (22), p. 738; Scibetta, A.G., Santangelo, S., Coleman, J., Functional analysis of the transcription repressor PLU-1/JARID1B (2007) Mol Cell Biol, 27 (20), pp. 7220-7235; Pal, S., Vishwanath, S.N., Erdjument-Bromage, H., Tempst, P., Sif, S., Human SWI/SNF-associ-ated PRMT5 methylates histone H3 arginine 8 and negatively regulates expression of ST7 and NM23 tumor suppressor genes (2004) Mol Cell Biol, 24 (21), pp. 9630-9645; Missiaglia, E., Donadelli, M., Palmieri, M., Crnogorac-Jurcevic, T., Scarpa, A., Lemoine, N.R., Growth delay of human pancreatic cancer cells by methylase inhibitor 5-aza-2'-deoxycytidine treatment is associated with activation of the interferon signalling pathway (2005) Oncogene, 24 (1), pp. 199-211; Lee, K.H., Park, J.W., Sung, H.S., PHF2 histone demethylase acts as a tumor suppressor in association with p53 in cancer (2015) Oncogene, 34 (22), pp. 2897-2909; Subtil-Rodriguez, A., Vazquez-Chavez, E., Ceballos-Chavez, M., The chromatin remodeller CHD8 is required for E2F-depen-dent transcription activation of S-phase genes (2014) Nucleic Acids Res, 42 (4), pp. 2185-2196; Rotili, D., Mai, A., Targeting Histone Demethylases: A New Avenue for the Fight against Cancer (2011) Genes Cancer, 2 (6), pp. 663-679; Jin, Y., Zhou, J., Xu, F., Targeting methyl-transferase PRMT5 eliminates leukemia stem cells in chronic myelogenous leukemia (2016) J Clin Invest, 126 (10), pp. 3961-3980; Yamane, K., Tateishi, K., Klose, R.J., PLU-1 is an H3K4 demethylase involved in transcriptional repression and breast cancer cell proliferation (2007) Mol Cell, 25 (6), pp. 801-812; Tang, B., Qi, G., Tang, F., JARID1B promotes metastasis and epithelial-mesenchy-mal transition via PTEN/AKT signaling in hepatocellular carcinoma cells (2015) Oncotarget, 6 (14), pp. 12723-12739; Zhang, T., Cooper, S., Brockdorff, N., The interplay of histone modifications-writers that read (2015) EMBO Rep, 16 (11), pp. 1467-1481; Quintas-Cardama, A., Santos, F.P., Garcia-Manero, G., Therapy with azanucleosides for myelodysplastic syndromes (2010) Nat Rev Clin Oncol, 7 (8), pp. 433-444; Jabbour, E., Short, N.J., Montalban-Bravo, G., Randomized phase 2 study of low-dose decitabine vs low-dose azacitidine in lower-risk MDS and MDS/MPN (2017) Blood, 130 (13), pp. 1514-1522; Kalac, M., Scotto, L., Marchi, E., HDAC inhibitors and decitabine are highly synergistic and associated with unique gene-expression and epigenetic profiles in models of DLBCL (2011) Blood, 118 (20), pp. 5506-5516; Laribi, K., Denizon, N., Ghnaya, H., Blastic plasmacytoid dendritic cell neoplasm: The first report of two cases treated by 5-azacytidine (2014) Eur J Haematol, 93 (1), pp. 81-85; Khwaja, R., Daly, A., Wong, M., Mahe, E., Cerquozzi, S., Owen, C., Azacitidine in the treatment of blastic plasmacytoid dendritic cell neoplasm: A report of 3 cases (2016) Leuk Lymphoma, 57 (11), pp. 2720-2722",
year = "2019",
doi = "10.3324/haematol.2018.202093",
language = "English",
volume = "104",
pages = "729--737",
journal = "Haematologica",
issn = "0390-6078",
publisher = "NLM (Medline)",
number = "4",

}

TY - JOUR

T1 - Blastic plasmacytoid dendritic cell neoplasm: Genomics mark epigenetic dysregulation as a primary therapeutic target

AU - Sapienza, M.R.

AU - Abate, F.

AU - Melle, F.

AU - Orecchioni, S.

AU - Fuligni, F.

AU - Etebari, M.

AU - Tabanelli, V.

AU - Laginestra, M.A.

AU - Pileri, A.

AU - Motta, G.

AU - Rossi, M.

AU - Agostinelli, C.

AU - Sabattini, E.

AU - Pimpinelli, N.

AU - Truni, M.

AU - Falini, B.

AU - Cerroni, L.

AU - Talarico, G.

AU - Piccioni, R.

AU - Amente, S.

AU - Indio, V.

AU - Tarantino, G.

AU - Brundu, F.

AU - Paulli, M.

AU - Berti, E.

AU - Facchetti, F.

AU - Dellino, G.I.

AU - Bertolini, F.

AU - Tripodo, C.

AU - Rabadan, R.

AU - Pileri, S.A.

N1 - Cited By :3 Export Date: 10 October 2019 CODEN: HAEMA Correspondence Address: Sapienza, M.R.; Hematopathology Unit, Department of Experimental, Diagnostic, and Specialty Medicine, S. Orsola-Malpighi Hospital, University of BolognaItaly; email: mariarosaria.sapienza@gmail.com Chemicals/CAS: azacitidine, 320-67-2, 52934-49-3; decitabine, 2353-33-5; romidepsin, 128517-07-7 Funding details: Hospital for Sick Children Funding details: Università di Bologna Funding details: Università degli Studi di Brescia Funding details: Fondazione IRCCS Policlinico San Matteo Funding details: Università degli Studi di Napoli Federico II Funding details: Royal College of Physicians and Surgeons of Canada Funding details: Department of Surgery Funding details: Associazione Italiana per la Ricerca sul Cancro, 5x1000 10007, IG 15762 Funding text 1: 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 and19Tumor Immunology Unit, Department of Health Science, Human Pathology Section, University of Palermo School of Medicine, Italy Funding text 2: The present work was supported by the AIRC grants IG 15762 and 5x1000 10007 “Genetics-driven targeted management of lymphoid malignancies” and the Grant “Innovative approaches to the diagnosis and pharmacogenetic-based therapies of primary hepatic tumours, peripheral B and T-cell lymphomas and lymphoblastic leukaemias” Strategic Programme 2010-2012 Regione Emilia Romagna - Università (all to SAP). References: Chaperot, L., Bendriss, N., Manches, O., Identification of a leukemic counterpart of the plasmacytoid dendritic cells (2001) Blood, 97 (10), pp. 3210-3217; Swerdlow, S.H., Campo, E., Hazzis, N.L., Facchetti F, Jones D, Petrella T. Blastic plasmacytoid dendritic cell neoplasm (2008) Swerdlow SH, pp. 145-147. , Campo E, Hazzis NL, et al., eds. WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press; Facchetti, F., Cigognetti, M., Fisogni, S., Rossi, G., Lonardi, S., Vermi, W., Neoplasms derived from plasmacytoid dendritic cells (2016) Mod Pathol, 29 (2), pp. 98-111; Garnache-Ottou, F., Feuillard, J., Ferrand, C., Extended diagnostic criteria for plasmacytoid dendritic cell leukaemia (2009) Br J Haematol, 145 (5), pp. 624-636; Pagano, L., Valentini, C.G., Pulsoni, A., Blastic plasmacytoid dendritic cell neoplasm with leukemic presentation: An Italian multicenter study (2013) Haematologica, 98 (2), pp. 239-246; Roos-Weil, D., Dietrich, S., Boumendil, A., Stem cell transplantation can provide durable disease control in blastic plasmacytoid dendritic cell neoplasm: A retrospective study from the European Group for Blood and Marrow Transplantation (2013) Blood, 121 (3), pp. 440-446; Pemmaraju, N., Blastic plasmacytoid dendritic cell neoplasm (2016) Clin Adv Hematol Oncol, 14 (4), pp. 220-222; Petrella, T., Dalac, S., Maynadie, M., CD4+ CD56+ cutaneous neoplasms: A distinct hematological entity? Groupe Francais d'Etude des Lymphomes Cutanes (GFELC) (1999) Am J Surg Pathol, 23 (2), pp. 137-146; Leroux, D., Mugneret, F., Callanan, M., CD4(+), CD56(+) DC2 acute leukemia is characterized by recurrent clonal chromosomal changes affecting 6 major targets: A study of 21 cases by the Groupe Francais de Cytogenetique Hematologique (2002) Blood, 99 (11), pp. 4154-4159; Reichard, K.K., Burks, E.J., Foucar, M.K., CD4(+) CD56(+) lineage-negative malignancies are rare tumors of plasmacytoid dendritic cells (2005) Am J Surg Pathol, 29 (10), pp. 1274-1283; Dijkman, R., van Doorn, R., Szuhai, K., Willemze, R., Vermeer, M.H., Tensen, C.P., Gene-expression profiling and array-based CGH classify CD4+CD56+ hematodermic neoplasm and cutaneous myelomonocytic leukemia as distinct disease entities (2007) Blood, 109 (4), pp. 1720-1727; Wiesner, T., Obenauf, A.C., Cota, C., Fried, I., Speicher, M.R., Cerroni, L., Alterations of the cell-cycle inhibitors p27(KIP1) and p16(INK4a) are frequent in blastic plasmacytoid dendritic cell neoplasms (2010) J Invest Dermatol, 130 (4), pp. 1152-1157; Agliano, A., Martin-Padura, I., Marighetti, P., Therapeutic effect of lenalidomide in a novel xenograft mouse model of human blastic NK cell lymphoma/blastic plasmacytoid dendritic cell neoplasm (2011) Clin Cancer Res, 17 (19), pp. 6163-6173; Jardin, F., Ruminy, P., Parmentier, F., TET2 and TP53 mutations are frequently observed in blastic plasmacytoid dendritic cell neoplasm (2011) Br J Haematol, 153 (3), pp. 413-416; Lucioni, M., Novara, F., Fiandrino, G., Twenty-one cases of blastic plasmacytoid dendritic cell neoplasm: Focus on biallelic locus 9p21.3 deletion (2011) Blood, 118 (17), pp. 4591-4594; Alayed, K., Patel, K.P., Konoplev, S., TET2 mutations, myelodysplastic features, and a distinct immunoprofile characterize blastic plasmacytoid dendritic cell neoplasm in the bone marrow (2013) Am J Hematol, 88 (12), pp. 1055-1061; Sapienza, M.R., Fuligni, F., Agostinelli, C., Molecular profiling of blastic plasmacytoid dendritic cell neoplasm reveals a unique pattern and suggests selective sensitivity to NF-kB pathway inhibition (2014) Leukemia, 28 (8), pp. 1606-1616; Philippe, L., Ceroi, A., Bole-Richard, E., Bortezomib as a new therapeutic approach for blastic plasmacytoid dendritic cell neoplasm (2017) Haematologica, 102 (11), pp. 1861-1868; Menezes, J., Acquadro, F., Wiseman, M., Exome sequencing reveals novel and recurrent mutations with clinical impact in blastic plasmacytoid dendritic cell neoplasm (2014) Leukemia, 28 (4), pp. 823-829; Stenzinger, A., Endris, V., Pfarr, N., Targeted ultra-deep sequencing reveals recurrent and mutually exclusive mutations of cancer genes in blastic plasmacytoid dendritic cell neoplasm (2014) Oncotarget, 5 (15), pp. 6404-6413; Emadali, A., Hoghoughi, N., Duley, S., Haploinsufficiency for NR3C1, the gene encoding the glucocorticoid receptor, in blastic plasmacytoid dendritic cell neoplasms (2016) Blood, 127 (24), pp. 3040-3053; Montero, J., Stephansky, J., Cai, T., Blastic Plasmacytoid Dendritic Cell Neoplasm Is Dependent on BCL2 and Sensitive to Venetoclax (2017) Cancer Discov, 7 (2), pp. 156-164; Ceroi, A., Masson, D., Roggy, A., LXR agonist treatment of blastic plasmacytoid dendritic cell neoplasm restores cholesterol efflux and triggers apoptosis (2016) Blood, 128 (23), pp. 2694-2707; Ceribelli, M., Hou, Z.E., Kelly, P.N., A Druggable TCF4-and BRD4-Dependent Transcriptional Network Sustains Malignancy in Blastic Plasmacytoid Dendritic Cell Neoplasm (2016) Cancer Cell, 30 (5), pp. 764-778; Angelot-Delettre, F., Roggy, A., Frankel, A.E., In vivo and in vitro sensitivity of blastic plasmacytoid dendritic cell neoplasm to SL-401, an interleukin-3 receptor targeted biologic agent (2015) Haematologica, 100 (2), pp. 223-230; Fanelli, M., Amatori, S., Barozzi, I., Pathology tissue-chromatin immunoprecipitation, coupled with high-throughput sequencing, allows the epigenetic profiling of patient samples (2010) Proc Natl Acad Sci U S A, 107 (50), pp. 21535-21540; Maeda, T., Murata, K., Fukushima, T., A novel plasmacytoid dendritic cell line, CAL-1, established from a patient with blastic natural killer cell lymphoma (2005) Int J Hematol, 81 (2), pp. 148-154; Ashburner, M., Ball, C.A., Blake, J.A., Gene ontology: Tool for the unification of biology. The Gene Ontology Consortium (2000) Nat Genet, 25 (1), pp. 25-29; Ward, A.F., Braun, B.S., Shannon, K.M., Targeting oncogenic Ras signaling in hematologic malignancies (2012) Blood, 120 (17), pp. 3397-3406; Guarini, A., Marinelli, M., Tavolaro, S., ATM gene alterations in chronic lymphocytic leukemia patients induce a distinct gene expression profile and predict disease progression (2012) Haematologica, 97 (1), pp. 47-55; Simon, M., Grandage, V.L., Linch, D.C., Khwaja, A., Constitutive activation of the Wnt/beta-catenin signalling pathway in acute myeloid leukaemia (2005) Oncogene, 24 (14), pp. 2410-2420; Kuo, Y.H., Zaidi, S.K., Gornostaeva, S., Komori, T., Stein, G.S., Castilla, L.H., Runx2 induces acute myeloid leukemia in cooperation with Cbfbeta-SMMHC in mice (2009) Blood, 113 (14), pp. 3323-3332; Togami, K., Madan, V., Li, J., Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) Harbors Frequent Splicesosome Mutations That Cause Aberrant RNA Splicing Affecting Genes Critical in pDC Differentiation and Function (2016) Blood, 128 (22), p. 738; Scibetta, A.G., Santangelo, S., Coleman, J., Functional analysis of the transcription repressor PLU-1/JARID1B (2007) Mol Cell Biol, 27 (20), pp. 7220-7235; Pal, S., Vishwanath, S.N., Erdjument-Bromage, H., Tempst, P., Sif, S., Human SWI/SNF-associ-ated PRMT5 methylates histone H3 arginine 8 and negatively regulates expression of ST7 and NM23 tumor suppressor genes (2004) Mol Cell Biol, 24 (21), pp. 9630-9645; Missiaglia, E., Donadelli, M., Palmieri, M., Crnogorac-Jurcevic, T., Scarpa, A., Lemoine, N.R., Growth delay of human pancreatic cancer cells by methylase inhibitor 5-aza-2'-deoxycytidine treatment is associated with activation of the interferon signalling pathway (2005) Oncogene, 24 (1), pp. 199-211; Lee, K.H., Park, J.W., Sung, H.S., PHF2 histone demethylase acts as a tumor suppressor in association with p53 in cancer (2015) Oncogene, 34 (22), pp. 2897-2909; Subtil-Rodriguez, A., Vazquez-Chavez, E., Ceballos-Chavez, M., The chromatin remodeller CHD8 is required for E2F-depen-dent transcription activation of S-phase genes (2014) Nucleic Acids Res, 42 (4), pp. 2185-2196; Rotili, D., Mai, A., Targeting Histone Demethylases: A New Avenue for the Fight against Cancer (2011) Genes Cancer, 2 (6), pp. 663-679; Jin, Y., Zhou, J., Xu, F., Targeting methyl-transferase PRMT5 eliminates leukemia stem cells in chronic myelogenous leukemia (2016) J Clin Invest, 126 (10), pp. 3961-3980; Yamane, K., Tateishi, K., Klose, R.J., PLU-1 is an H3K4 demethylase involved in transcriptional repression and breast cancer cell proliferation (2007) Mol Cell, 25 (6), pp. 801-812; Tang, B., Qi, G., Tang, F., JARID1B promotes metastasis and epithelial-mesenchy-mal transition via PTEN/AKT signaling in hepatocellular carcinoma cells (2015) Oncotarget, 6 (14), pp. 12723-12739; Zhang, T., Cooper, S., Brockdorff, N., The interplay of histone modifications-writers that read (2015) EMBO Rep, 16 (11), pp. 1467-1481; Quintas-Cardama, A., Santos, F.P., Garcia-Manero, G., Therapy with azanucleosides for myelodysplastic syndromes (2010) Nat Rev Clin Oncol, 7 (8), pp. 433-444; Jabbour, E., Short, N.J., Montalban-Bravo, G., Randomized phase 2 study of low-dose decitabine vs low-dose azacitidine in lower-risk MDS and MDS/MPN (2017) Blood, 130 (13), pp. 1514-1522; Kalac, M., Scotto, L., Marchi, E., HDAC inhibitors and decitabine are highly synergistic and associated with unique gene-expression and epigenetic profiles in models of DLBCL (2011) Blood, 118 (20), pp. 5506-5516; Laribi, K., Denizon, N., Ghnaya, H., Blastic plasmacytoid dendritic cell neoplasm: The first report of two cases treated by 5-azacytidine (2014) Eur J Haematol, 93 (1), pp. 81-85; Khwaja, R., Daly, A., Wong, M., Mahe, E., Cerquozzi, S., Owen, C., Azacitidine in the treatment of blastic plasmacytoid dendritic cell neoplasm: A report of 3 cases (2016) Leuk Lymphoma, 57 (11), pp. 2720-2722

PY - 2019

Y1 - 2019

N2 - 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

AB - 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

KW - azacitidine

KW - decitabine

KW - romidepsin

KW - transcriptome

KW - adult

KW - animal experiment

KW - animal model

KW - animal tissue

KW - Article

KW - CAL-1 [Human melanoma] cell line

KW - chromatin immunoprecipitation

KW - clinical article

KW - controlled study

KW - dendritic cell sarcoma

KW - epigenetics

KW - female

KW - gene mutation

KW - hematopoietic stem cell transplantation

KW - histone methylation

KW - human

KW - immune dysregulation

KW - immunohistochemistry

KW - male

KW - middle aged

KW - mouse

KW - nonhuman

KW - plasmacytoid dendritic cell

KW - protein expression

KW - RNA sequence

KW - Sanger sequencing

KW - single nucleotide polymorphism

KW - somatic mutation

KW - upregulation

KW - whole exome sequencing

U2 - 10.3324/haematol.2018.202093

DO - 10.3324/haematol.2018.202093

M3 - Article

VL - 104

SP - 729

EP - 737

JO - Haematologica

JF - Haematologica

SN - 0390-6078

IS - 4

ER -