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

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

TODARO, MARIA;LANDRA, INDIRA;TABBO', FABRIZIO;BARRECA, Antonella;ALIBERTI, SABRINA;DI GIACOMO, FILOMENA;CRESCENZO, RAMONA;BESSONE, LUCA;LONGO, DARIO LIVIO;AIME, Silvio;PIVA, Roberto;INGHIRAMI, Giorgio
2015

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
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Animals; Blotting, Western; Flow Cytometry; Gene Expression Profiling; High-Throughput Nucleotide Sequencing; Humans; Immunoprecipitation; In Situ Hybridization, Fluorescence; Lymphoma, Large-Cell, Anaplastic; Mice; Mice, Inbred NOD; NF-kappa B; Proteasome Inhibitors; Proto-Oncogene Proteins c-myc; RNA, Messenger; Real-Time Polymerase Chain Reaction; Receptor Protein-Tyrosine Kinases; Repressor Proteins; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; TNF Receptor-Associated Factor 1; Translocation, Genetic; Tumor Cells, Cultured; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays; Drug Resistance, Neoplasm; Hematology; Cancer Research; Anesthesiology and Pain Medicine; Medicine (all)
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.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1532761
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