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.
|Titolo:||A novel patient-derived tumorgraft model with TRAF1-ALK anaplastic large-cell lymphoma translocation|
|Parole Chiave:||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; Positive Regulatory Domain I-Binding Factor 1; 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; Oncology; Cancer Research|
|Settore Scientifico Disciplinare:||Settore MED/15 - Malattie del Sangue|
|Data di pubblicazione:||giu-2015|
|Digital Object Identifier (DOI):||10.1038/leu.2014.347|
|Appare nelle tipologie:||01 - Articolo su periodico|