title: A novel patient-derived tumorgraft model with TRAF1-ALK anaplastic large-cell lymphoma translocation.
abstract: 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.
authors.affiliation: 1] Department of Control and Computer Engineering, Politecnico di Torino, Turin, Italy [2] Department of Biomedical Informatics, Center for Computational Biology and Bioinformatics, Columbia University, New York, NY, USA [3] Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Turin, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Abate
authors.affiliation: Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Turin, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Todaro
authors.affiliation: Department of Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: J-A
authors.initials: JA
authors.lastname: van der Krogt
authors.affiliation: 1] Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Turin, Italy [2] Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Boi
authors.affiliation: Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Turin, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Landra
authors.affiliation: Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Turin, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Machiorlatti
authors.affiliation: Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Turin, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Tabbò
authors.affiliation: Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Turin, Italy.
authors.forename: K
authors.initials: K
authors.lastname: Messana
authors.affiliation: Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Turin, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Abele
authors.affiliation: Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Turin, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Barreca
authors.affiliation: Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Turin, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Novero
authors.affiliation: Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Turin, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Gaudiano
authors.affiliation: Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Turin, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Aliberti
authors.affiliation: Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Turin, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Di Giacomo
authors.affiliation: Translational Cell and Tissue Research, KU Leuven, Department of Pathology, UZ Leuven, Leuven, Belgium.
authors.forename: T
authors.initials: T
authors.lastname: Tousseyn
authors.affiliation: Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Turin, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Lasorsa
authors.affiliation: Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Turin, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Crescenzo
authors.affiliation: Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Turin, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Bessone
authors.affiliation: Department of Control and Computer Engineering, Politecnico di Torino, Turin, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Ficarra
authors.affiliation: Department of Control and Computer Engineering, Politecnico di Torino, Turin, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Acquaviva
authors.affiliation: Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Rinaldi
authors.affiliation: Pathology & Lymphoid Malignancies Units, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Ponzoni
authors.affiliation: Molecular Imaging Center, Department of Chemistry IFM and Molecular Imaging Center, University of Torino, Turin, Italy.
authors.forename: D L
authors.initials: DL
authors.lastname: Longo
authors.affiliation: Molecular Imaging Center, Department of Chemistry IFM and Molecular Imaging Center, University of Torino, Turin, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Aime
authors.affiliation: Teva Pharmaceuticals, Inc, North Wales, PA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Cheng
authors.affiliation: Teva Pharmaceuticals, Inc, North Wales, PA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Ruggeri
authors.affiliation: Institute of Hematology and Medical Oncology L. and A. Seràgnoli, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: P P
authors.initials: PP
authors.lastname: Piccaluga
authors.affiliation: Institute of Hematology and Medical Oncology L. and A. Seràgnoli, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Pileri
authors.affiliation: Institute of Hematology, University of Perugia, Ospedale S. Maria della Misericordia, S. Andrea delle Fratte, Perugia, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Tiacci
authors.affiliation: Institute of Hematology, University of Perugia, Ospedale S. Maria della Misericordia, S. Andrea delle Fratte, Perugia, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Falini
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
authors.forename: B
authors.initials: B
authors.lastname: Pera-Gresely
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
authors.forename: L
authors.initials: L
authors.lastname: Cerchietti
authors.affiliation: The Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: J
authors.initials: J
authors.lastname: Iqbal
authors.affiliation: Department of Pathology, City of Hope Medical Center, Duarte, CA, USA.
authors.forename: W C
authors.initials: WC
authors.lastname: Chan
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA.
authors.forename: L D
authors.initials: LD
authors.lastname: Shultz
authors.affiliation: 1] Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland [2] IDSIA Dalle Molle Institute for Artificial Intelligence, Manno, Switzerland [3] SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors.forename: I
authors.initials: I
authors.lastname: Kwee
authors.affiliation: 1] Department of Control and Computer Engineering, Politecnico di Torino, Turin, Italy [2] Department of Pathology, and NYU Cancer Center, New York University School of Medicine, New York, NY, USA.
authors.forename: R
authors.initials: R
authors.lastname: Piva
authors.affiliation: Department of Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: I
authors.initials: I
authors.lastname: Wlodarska
authors.affiliation: Department of Biomedical Informatics, Center for Computational Biology and Bioinformatics, Columbia University, New York, NY, USA.
authors.forename: R
authors.initials: R
authors.lastname: Rabadan
authors.affiliation: 1] Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland [2] Lymphoma Unit, IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
authors.forename: F
authors.initials: F
authors.lastname: Bertoni
authors.affiliation: 1] Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Turin, Italy [2] Department of Pathology, and NYU Cancer Center, New York University School of Medicine, New York, NY, USA [3] Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA.
authors.forename: G
authors.initials: G
authors.lastname: Inghirami
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D015153:Blotting, Western; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D047468:Immunoprecipitation; D017404:In Situ Hybridization, Fluorescence; D017728:Lymphoma, Large-Cell, Anaplastic / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D051379:Mice; D016688:Mice, Inbred NOD; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D000074462:Positive Regulatory Domain I-Binding Factor 1; D061988:Proteasome Inhibitors / Q000494:pharmacology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D047990:TNF Receptor-Associated Factor 1 / Q000235:genetics* / Q000378:metabolism; D014178:Translocation, Genetic / Q000235:genetics*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C489427:MYC protein, human; D016328:NF-kappa B; D061988:Proteasome Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D012097:Repressor Proteins; D047990:TNF Receptor-Associated Factor 1; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C087042:PRDM1 protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases