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

F Abate; M Todaro; J-A van der Krogt; M Boi; I Landra; R Machiorlatti; F Tabbò; K Messana; C Abele; A Barreca; D Novero; M Gaudiano; S Aliberti; F Di Giacomo; T Tousseyn; E Lasorsa; R Crescenzo; L Bessone; E Ficarra; A Acquaviva; A Rinaldi; M Ponzoni; D L Longo; S Aime; M Cheng; B Ruggeri; P P Piccaluga; S Pileri; E Tiacci; B Falini; B Pera-Gresely; L Cerchietti; J Iqbal; W C Chan; L D Shultz; I Kwee; R Piva; I Wlodarska; R Rabadan; F Bertoni; G Inghirami; European T-cell Lymphoma Study Group

doi:10.1038/leu.2014.347

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

Leukemia. 2015 Jun;29(6):1390-401. doi: 10.1038/leu.2014.347. Epub 2014 Dec 23.

Authors

F Abate¹, M Todaro², J-A van der Krogt³, M Boi⁴, I Landra², R Machiorlatti², F Tabbò², K Messana², C Abele², A Barreca², D Novero², M Gaudiano², S Aliberti², F Di Giacomo², T Tousseyn⁵, E Lasorsa², R Crescenzo², L Bessone², E Ficarra⁶, A Acquaviva⁶, A Rinaldi⁷, M Ponzoni⁸, D L Longo⁹, S Aime⁹, M Cheng¹⁰, B Ruggeri¹⁰, P P Piccaluga¹¹, S Pileri¹¹, E Tiacci¹², B Falini¹², B Pera-Gresely¹³, L Cerchietti¹³, J Iqbal¹⁴, W C Chan¹⁵, L D Shultz¹⁶, I Kwee¹⁷, R Piva¹⁸, I Wlodarska³, R Rabadan¹⁹, F Bertoni²⁰, G Inghirami²¹; European T-cell Lymphoma Study Group

Collaborators

European T-cell Lymphoma Study Group:
Cristina Abele, Luca Bessone, Antonella Barreca, Michela Boi, Federica Cavallo, 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 Scafò, Elisa Spaccarotella, Fabrizio Tabbò, Maria Todaro, Ivana Ubezzi, Susanna Urigu, Domenico Novero, Annalisa Chiapella, Umberto Vitolo, Francesco Abate, Elisa Ficarra, Andrea Acquaviva, Luca Agnelli, Antonino Neri, Anna Caliò Marco Chilosi, Alberto Zamó, Fabio Facchetti, Silvia Lonardi, Anna De Chiara, Franco Fulciniti, Andrés Ferreri, Maurilio Ponzoni, Claudio Agostinelli, Pier Paolo Piccaluga, Stefano Pileri, Brunangelo Falini, Enrico Tiacci, Peter Van Loo, Thomas Tousseyn, Christiane De Wolf-Peeters, Eva Geissinger, Hans Konrad Muller-Hermelink, Andreas Rosenwald, Miguel Angel Piris, Maria E Rodriguez, Francesco Bertoni, Andrea Rinaldi, Ivo Kwee, Carlos Chiattone, Roberto Antonio Pinto Paes

Affiliations

¹ 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.
² Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Turin, Italy.
³ Department of Human Genetics, KU Leuven, Leuven, Belgium.
⁴ 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.
⁵ Translational Cell and Tissue Research, KU Leuven, Department of Pathology, UZ Leuven, Leuven, Belgium.
⁶ Department of Control and Computer Engineering, Politecnico di Torino, Turin, Italy.
⁷ Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.
⁸ Pathology & Lymphoid Malignancies Units, San Raffaele Scientific Institute, Milan, Italy.
⁹ Molecular Imaging Center, Department of Chemistry IFM and Molecular Imaging Center, University of Torino, Turin, Italy.
¹⁰ Teva Pharmaceuticals, Inc, North Wales, PA, USA.
¹¹ Institute of Hematology and Medical Oncology L. and A. Seràgnoli, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
¹² Institute of Hematology, University of Perugia, Ospedale S. Maria della Misericordia, S. Andrea delle Fratte, Perugia, Italy.
¹³ Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
¹⁴ The Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.
¹⁵ Department of Pathology, City of Hope Medical Center, Duarte, CA, USA.
¹⁶ The Jackson Laboratory, Bar Harbor, ME, USA.
¹⁷ 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.
¹⁸ 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.
¹⁹ Department of Biomedical Informatics, Center for Computational Biology and Bioinformatics, Columbia University, New York, NY, USA.
²⁰ 1] Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland [2] Lymphoma Unit, IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
²¹ 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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Anaplastic Lymphoma Kinase
Animals
Blotting, Western
Drug Resistance, Neoplasm*
Flow Cytometry
Gene Expression Profiling
High-Throughput Nucleotide Sequencing
Humans
Immunoprecipitation
In Situ Hybridization, Fluorescence
Lymphoma, Large-Cell, Anaplastic / drug therapy
Lymphoma, Large-Cell, Anaplastic / genetics*
Lymphoma, Large-Cell, Anaplastic / mortality
Mice
Mice, Inbred NOD
NF-kappa B / genetics
NF-kappa B / metabolism*
Positive Regulatory Domain I-Binding Factor 1
Proteasome Inhibitors / pharmacology
Proto-Oncogene Proteins c-myc / genetics
Proto-Oncogene Proteins c-myc / metabolism
RNA, Messenger / genetics
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
Signal Transduction
TNF Receptor-Associated Factor 1 / genetics*
TNF Receptor-Associated Factor 1 / metabolism
Translocation, Genetic / genetics*
Tumor Cells, Cultured
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / metabolism
Xenograft Model Antitumor Assays

Substances

MYC protein, human
NF-kappa B
Proteasome Inhibitors
Proto-Oncogene Proteins c-myc
RNA, Messenger
Repressor Proteins
TNF Receptor-Associated Factor 1
TP53 protein, human
Tumor Suppressor Protein p53
PRDM1 protein, human
Positive Regulatory Domain I-Binding Factor 1
ALK protein, human
Alk protein, mouse
Anaplastic Lymphoma Kinase
Receptor Protein-Tyrosine Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding