Crescenzo Ramona, Abate Francesco, Lasorsa Elena, Tabbo' Fabrizio, Gaudiano Marcello, Chiesa Nicoletta, Di Giacomo Filomena, Spaccarotella Elisa, Barbarossa Luigi, Ercole Elisabetta, Todaro Maria, Boi Michela, Acquaviva Andrea, Ficarra Elisa, Novero Domenico, Rinaldi Andrea, Tousseyn Thomas, Rosenwald Andreas, Kenner Lukas, Cerroni Lorenzo, Tzankov Alexander, Ponzoni Maurilio, Paulli Marco, Weisenburger Dennis, Chan Wing C, Iqbal Javeed, Piris Miguel A, Zamo' Alberto, Ciardullo Carmela, Rossi Davide, Gaidano Gianluca, Pileri Stefano, Tiacci Enrico, Falini Brunangelo, Shultz Leonard D, Mevellec Laurence, Vialard Jorge E, Piva Roberto, Bertoni Francesco, Rabadan Raul, Inghirami Giorgio
Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies, University of Torino, 10126 Torino, Italy; Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10021, USA.
Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies, University of Torino, 10126 Torino, Italy; Department of Control and Computer Engineering, Politecnico di Torino, 10129 Torino, Italy; Department of Biomedical Informatics and Department of Systems Biology, Center for Computational Biology and Bioinformatics, Columbia University, New York, NY 10027, USA.
Cancer Cell. 2015 Apr 13;27(4):516-32. doi: 10.1016/j.ccell.2015.03.006.
A systematic characterization of the genetic alterations driving ALCLs has not been performed. By integrating massive sequencing strategies, we provide a comprehensive characterization of driver genetic alterations (somatic point mutations, copy number alterations, and gene fusions) in ALK(-) ALCLs. We identified activating mutations of JAK1 and/or STAT3 genes in ∼20% of 88 [corrected] ALK(-) ALCLs and demonstrated that 38% of systemic ALK(-) ALCLs displayed double lesions. Recurrent chimeras combining a transcription factor (NFkB2 or NCOR2) with a tyrosine kinase (ROS1 or TYK2) were also discovered in WT JAK1/STAT3 ALK(-) ALCL. All these aberrations lead to the constitutive activation of the JAK/STAT3 pathway, which was proved oncogenic. Consistently, JAK/STAT3 pathway inhibition impaired cell growth in vitro and in vivo.
尚未对驱动间变性大细胞淋巴瘤（ALCLs）的基因改变进行系统的特征描述。通过整合大规模测序策略，我们全面描述了ALK（-）ALCLs中驱动基因改变（体细胞点突变、拷贝数改变和基因融合）的特征。我们在88例[校正后]ALK（-）ALCLs中约20%发现了JAK1和/或STAT3基因的激活突变，并证明38%的系统性ALK（-）ALCLs存在双重病变。在野生型JAK1/STAT3的ALK（-）ALCL中还发现了将转录因子（NFkB2或NCOR2）与酪氨酸激酶（ROS1或TYK2）结合的复发性嵌合体。所有这些异常都导致JAK/STAT3通路的组成性激活，这被证明具有致癌性。同样，JAK/STAT3通路抑制在体外和体内均损害细胞生长。
