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
1] Department of Control and Computer Engineering, Politecnico di Torino, Turin, Italy [2] Department of Biomedical Informatics, Center for Computational Biology and Bioinformatics, Columbia University, New York, NY, USA [3] Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Turin, Italy.
Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Turin, Italy.
Leukemia. 2015 Jun;29(6):1390-401. doi: 10.1038/leu.2014.347. Epub 2014 Dec 23.
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.
尽管携带间变性淋巴瘤激酶（ALK）的间变性大细胞淋巴瘤（ALCL）预后相对较好，但仍存在侵袭性类型。我们在一名患有白血病性ALK阳性ALCL（ALCL-11）的患者中鉴定出一种新型易位，导致TRAF1和ALK基因融合。为了揭示导致高级别ALCL的机制，我们建立了一个源自人类患者的肿瘤移植（hPDT）系。对原代细胞和PDT细胞的分子特征分析表明ALK和核因子κB（NFκB）信号通路被激活。对ALCL-11的基因组研究显示TP53缺失以及淋巴瘤细胞在体内的亚克隆扩增，这些细胞缺乏PRDM1/Blimp1并携带c-MYC基因扩增。用蛋白酶体抑制剂处理TRAF1-ALK细胞导致p50/p52下调和淋巴瘤生长受抑制。此外，一个NFκB基因集分类器将ALCL分为具有不同临床结局的不同亚组。尽管一种选择性ALK抑制剂（CEP28122）使hPDT小鼠产生了显著的临床反应，但疾病仍无法根除。这些数据表明NFκB信号通路的激活促成了TRAF1-ALK ALCL的肿瘤表型。ALCL hPDT是验证可成药分子作用、预测治疗反应和实施患者特异性治疗的宝贵工具。
