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 2015-06, Vol.29 (6), p.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: Article
Language:English
Subjects:
Anaplastic large-cell lymphoma
Animals
Blotting, Western
c-Myc protein
Care and treatment
Cell activation
Development and progression
Drug Resistance, Neoplasm
Flow Cytometry
Gene amplification
Gene Expression Profiling
Genetic aspects
Genetic regulation
Health aspects
High-Throughput Nucleotide Sequencing
Humans
Immunoprecipitation
In Situ Hybridization, Fluorescence
In vivo methods and tests
Innovations
Kinases
Leukemia
Lymphoma
Lymphoma, Large-Cell, Anaplastic - drug therapy
Lymphoma, Large-Cell, Anaplastic - genetics
Lymphoma, Large-Cell, Anaplastic - mortality
Lymphomas
Mice
Mice, Inbred NOD
Molecular targeted therapy
Myc protein
NF-kappa B - genetics
NF-kappa B - metabolism
NF-κB protein
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
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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.
ISSN:0887-6924
1476-5551
DOI:10.1038/leu.2014.347