A novel patient-derived tumorgraft model with TRAF1-ALK anaplastic large-cell lymphoma translocation

Although anaplastic large-cell lymphomas (ALCL) carrying anaplastic lymphoma kinase (ALK) have a relatively good prognosis, aggressive forms exist. We have identified a novel translocation, causing the fusion of the TRAF1 and ALK genes, in one patient who presented with a leukemic ALK+ ALCL (ALCL-11...

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Published in:	Leukemia Vol. 29; no. 6; pp. 1390 - 1401
Main Authors:	Abate, F, Todaro, M, van der Krogt, J-A, Boi, M, Landra, I, Machiorlatti, R, Tabbò, F, Messana, K, Abele, C, Barreca, A, Novero, D, Gaudiano, M, Aliberti, S, Di Giacomo, F, Tousseyn, T, Lasorsa, E, Crescenzo, R, Bessone, L, Ficarra, E, Acquaviva, A, Rinaldi, A, Ponzoni, M, Longo, D L, Aime, S, Cheng, M, Ruggeri, B, Piccaluga, P P, Pileri, S, Tiacci, E, Falini, B, Pera-Gresely, B, Cerchietti, L, Iqbal, J, Chan, W C, Shultz, L D, Kwee, I, Piva, R, Wlodarska, I, Rabadan, R, Bertoni, F, Inghirami, G
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-06-2015 Nature Publishing Group
Subjects:	13/95 38 45 59 631/67/70 692/308/2778 692/699/67/1990/291/1621/1916 692/699/67/68 Anaplastic large-cell lymphoma Animals Blotting, Western c-Myc protein Cancer Research Care and treatment Cell activation Critical Care Medicine Development and progression Drug Resistance, Neoplasm Flow Cytometry Gene amplification Gene Expression Profiling Genetic aspects Genetic regulation Health aspects Hematology High-Throughput Nucleotide Sequencing Humans Immunoprecipitation In Situ Hybridization, Fluorescence In vivo methods and tests Innovations Intensive Internal Medicine Kinases Leukemia Lymphoma Lymphoma, Large-Cell, Anaplastic - drug therapy Lymphoma, Large-Cell, Anaplastic - genetics Lymphoma, Large-Cell, Anaplastic - mortality Lymphomas Medicine Medicine & Public Health Mice Mice, Inbred NOD Molecular targeted therapy Myc protein NF-kappa B - genetics NF-kappa B - metabolism NF-κB protein Oncology original-article p53 Protein Patients Phenotypes Phosphotransferases Positive Regulatory Domain I-Binding Factor 1 Proteasome inhibitors Proteasome Inhibitors - pharmacology Protein-tyrosine kinase Proto-Oncogene Proteins c-myc - genetics Proto-Oncogene Proteins c-myc - metabolism Real-Time Polymerase Chain Reaction Receptor Protein-Tyrosine Kinases - genetics Receptor Protein-Tyrosine Kinases - metabolism Repressor Proteins - genetics Repressor Proteins - metabolism Reverse Transcriptase Polymerase Chain Reaction RNA, Messenger - genetics Signal Transduction TNF Receptor-Associated Factor 1 - genetics TNF Receptor-Associated Factor 1 - metabolism Transcription factors Translocation Translocation (Genetics) Translocation, Genetic - genetics Tumor Cells, Cultured Tumor Suppressor Protein p53 - genetics Tumor Suppressor Protein p53 - metabolism Xenograft Model Antitumor Assays Italy
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Summary:	Although anaplastic large-cell lymphomas (ALCL) carrying anaplastic lymphoma kinase (ALK) have a relatively good prognosis, aggressive forms exist. We have identified a novel translocation, causing the fusion of the TRAF1 and ALK genes, in one patient who presented with a leukemic ALK+ ALCL (ALCL-11). To uncover the mechanisms leading to high-grade ALCL, we developed a human patient-derived tumorgraft (hPDT) line. Molecular characterization of primary and PDT cells demonstrated the activation of ALK and nuclear factor kB (NFkB) pathways. Genomic studies of ALCL-11 showed the TP53 loss and the in vivo subclonal expansion of lymphoma cells, lacking PRDM1/Blimp1 and carrying c- MYC gene amplification. The treatment with proteasome inhibitors of TRAF1-ALK cells led to the downregulation of p50/p52 and lymphoma growth inhibition. Moreover, a NFkB gene set classifier stratified ALCL in distinct subsets with different clinical outcome. Although a selective ALK inhibitor (CEP28122) resulted in a significant clinical response of hPDT mice, nevertheless the disease could not be eradicated. These data indicate that the activation of NFkB signaling contributes to the neoplastic phenotype of TRAF1-ALK ALCL. ALCL hPDTs are invaluable tools to validate the role of druggable molecules, predict therapeutic responses and implement patient specific therapies.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Current addresses: Mangeng Cheng, In Vitro Pharmacology, Merck Research Laboratory, BMB11-138, 33 Avenue Louis Pasteur, Boston, MA 02115. < mangeng.cheng@merck.com> The European T-Cell Lymphoma Study Group: Italy: Cristina Abele, Luca Bessone, Antonella Barreca, Michela Boi, Nicoletta Chiesa, Ramona Crescenzo, Antonella Fienga, Marcello Gaudiano, Filomena di Giacomo, Giorgio Inghirami, Indira Landra, Elena Lasorsa, Rodolfo Marchiorlatti, Barbara Martinoglio, Enzo Medico, Gian Battista Ferrero, Katia Messana, Elisabetta Mereu, Elisa Pellegrino, Roberto Piva, Irene Scafo’, Elisa Spaccarotella, Fabrizio Tabbo’, Maria Todaro, Ivana Ubezzi, Susanna Urigu (Azienda Ospedaliera Città della Salute e della Scienza di Torino, University of Turin); Antonella Barreca, Domenico Novero, Annalisa Chiapella and Umberto Vitolo (ASO Molinette, and San Luigi Gonzaga Torino); Francesco Abate, Elisa Ficarra, Andrea Acquaviva (Politecnico di Torino); Luca Agnelli and Antonino Neri (University of Milan); Anna Caliò Marco Chilosi and Alberto Zamó (University of Verona); Fabio Facchetti and Silvia Lonardi (University of Brescia); Anna De Chiara and Franco Fulciniti (National Cancer Institute, Naples); Claudio Doglioni, Andrés Ferreri and Maurilio Ponzoni (San Raffaele Institute, Milan); Claudio Agostinelli, Pier Paolo Piccaluga and Stefano Pileri (University of Bologna); Brunangelo Falini and Enrico Tiacci (University of Perugia). Belgium: Peter Van Loo, Thomas Tousseyn, and Christiane De Wolf-Peeters (University of Leuven); Germany: Eva Geissinger, Hans Konrad Muller-Hermelink and Andreas Rosenwald, (University of Wuerzburg); Spain: Miguel Angel Piris and Maria E. Rodriguez (Hospital Universitario Marqués de Valdecilla, IFIMAV, Santander and Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Madrid); Switzerland: Francesco Bertoni, Andrea Rinaldi, Ivo Kwee (Institute of Oncology Research, Bellinzona). These authors contributed equally
ISSN:	0887-6924 1476-5551
DOI:	10.1038/leu.2014.347