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

TitleA novel patient-derived tumorgraft model with TRAF1-ALK anaplastic large-cell lymphoma translocation.
Publication TypeJournal Article
Year of Publication2015
AuthorsAbate 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 DL, Aime S, Cheng M, Ruggeri B, Piccaluga PP, Pileri S, Tiacci E, Falini B, Pera-Gresely B, Cerchietti L, Iqbal J, Chan WC, Shultz LD, Kwee I, Piva R, Wlodarska I, Rabadan R, Bertoni F, Inghirami G
Corporate AuthorsEuropean T-Cell Lymphoma Study Group
Date Published2015 Jun
KeywordsAnaplastic 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, Mice, Mice, Inbred NOD, NF-kappa B, Positive Regulatory Domain I-Binding Factor 1, Proteasome Inhibitors, Proto-Oncogene Proteins c-myc, Real-Time Polymerase Chain Reaction, Receptor Protein-Tyrosine Kinases, Repressor Proteins, Reverse Transcriptase Polymerase Chain Reaction, RNA, Messenger, Signal Transduction, TNF Receptor-Associated Factor 1, Translocation, Genetic, Tumor Cells, Cultured, Tumor Suppressor Protein p53, Xenograft Model Antitumor Assays

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.

Alternate JournalLeukemia
PubMed ID25533804
PubMed Central IDPMC4864432
Grant List1R01CA164152-01 / CA / NCI NIH HHS / United States
P50 MH094267 / MH / NIMH NIH HHS / United States
P30 CA034196 / CA / NCI NIH HHS / United States
U54 CA121852 / CA / NCI NIH HHS / United States
CA034196 / CA / NCI NIH HHS / United States
1 P50 MH094267-01 / MH / NIMH NIH HHS / United States
R01 CA164152 / CA / NCI NIH HHS / United States
1 U54 CA121852-05 / CA / NCI NIH HHS / United States
Related Faculty: 
Giorgio Inghirami, M.D.

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