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

作者：Abate F; Todaro M; van der Krogt J A; Boi M; Landra I; Machiorlatti R; Tabbo 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

来源：Leukemia, 2015, 29(6): 1390-1401.

DOI：10.1038/leu.2014.347

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 kappa B (NF kappa B) 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 NF kappa B 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 NF kappa B 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.

• 出版日期2015-6