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    Cancer cell. 2015 Apr 15. pii: S1535-6108(15)00094-X. doi: 10.1016/j.ccell.2015.03.006
    Convergent mutations and kinase fusions lead to oncogenic STAT3 activation in anaplastic large cell lymphoma.
    Crescenzo R1,  Abate F2,  Lasorsa E3,  Tabbo' F4,  Gaudiano M5,  Chiesa N6,  Di Giacomo F7,  Spaccarotella E8,  Barbarossa L9,  Ercole E10,  Todaro M11,  Boi M12,  Acquaviva A13,  Ficarra E14,  Novero D15,  Rinaldi A16,  Tousseyn T17,  Rosenwald A18,  Kenner L19,  Cerroni L20,  Tzankov A21,  Ponzoni M22,  Paulli M23,  Weisenburger D24,  Chan WC25,  Iqbal J26,  Piris MA27,  Zamo' A28,  Ciardullo C29,  Rossi D30,  Gaidano G31,  Pileri S32,  Tiacci E33,  Falini B34,  Shultz LD35,  Mevellec L36,  Vialard JE37,  Piva R38,  Bertoni F39,  Rabadan R40,  Inghirami G41
    Author information
    1Department 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.
    2Department 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.
    3Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies, University of Torino, 10126 Torino, Italy.
    4Department 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.
    5Department 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.
    6Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies, University of Torino, 10126 Torino, Italy.
    7Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies, University of Torino, 10126 Torino, Italy.
    8Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies, University of Torino, 10126 Torino, Italy.
    9Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies, University of Torino, 10126 Torino, Italy.
    10Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies, University of Torino, 10126 Torino, Italy.
    11Department 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.
    12Department 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.
    13Department of Control and Computer Engineering, Politecnico di Torino, 10129 Torino, Italy.
    14Department of Control and Computer Engineering, Politecnico di Torino, 10129 Torino, Italy.
    15Department of Pathology, A.O. Città della Salute e della Scienza (Molinette), 10126 Torino, Italy.
    16Lymphoma and Genomics Research Program, Institute of Oncology Research, 6500 Bellinzona, Switzerland.
    17Translational Cell and Tissue Research Lab, KU Leuven, 3000 Leuven, Belgium.
    18Institute of Pathology, University of Würzburg and Comprehensive Cancer Center Mainfranken, 97080 Würzburg, Germany.
    19Ludwing Boltzmann Institute for Cancer Research, 1090 Vienna, Austria.
    20Research Unit Dermatopathology of the Medical University of Graz, 8036 Graz, Austria.
    21Institute of Pathology, University Hospital Basel, 4031 Basel, Switzerland.
    22Pathology & Lymphoid Malignancies Units, San Raffaele Scientific Institute, 20132 Milan, Italy.
    23Department of Human Pathology, University of Pavia and Scientific Institute Fondazione Policlinico San Matteo, 27100 Pavia, Italy.
    24Department of Pathology, City of Hope Medical Center, Duarte, CA 91010, USA.
    25Department of Pathology, City of Hope Medical Center, Duarte, CA 91010, USA.
    26Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
    27Cancer Genomics, Instituto de Formación e Investigación Marqués de Valdecilla and Department of Pathology, Hospital Universitario Marqués de Valdecilla, 39008 Santander, Spain.
    28Department of Pathology and Diagnostics, University of Verona, 37134 Verona, Italy.
    29Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, 28100 Novara, Italy.
    30Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, 28100 Novara, Italy.
    31Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, 28100 Novara, Italy.
    32European Institute of Oncology, 20141 Milano, Italy; Bologna University School of Medicine, 40126 Bologna, Italy.
    33Institute of Hematology-Centro di Ricerche Onco-Ematologiche (CREO), Ospedale S. Maria della Misericordia, University of Perugia, 06100 Perugia, Italy.
    34Institute of Hematology-Centro di Ricerche Onco-Ematologiche (CREO), Ospedale S. Maria della Misericordia, University of Perugia, 06100 Perugia, Italy.
    35The Jackson Laboratory, Bar Harbor, ME 04609, USA.
    36Janssen Research & Development, a Division of Janssen-Cilag, Campus de Maigremont, CS10615, 27106 Val-de-Reuil Cedex, France.
    37Janssen Research & Development, a Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium.
    38Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies, University of Torino, 10126 Torino, Italy; Department of Pathology and NYU Cancer Center, New York University School of Medicine, New York, NY 10016, USA.
    39Lymphoma and Genomics Research Program, Institute of Oncology Research, 6500 Bellinzona, Switzerland; Oncology Institute of Southern Switzerland, 6500 Bellinzona, Switzerland.
    40Department of Biomedical Informatics and Department of Systems Biology, Center for Computational Biology and Bioinformatics, Columbia University, New York, NY 10027, USA. Electronic address: rr2579@cumc.columbia.edu.
    41Department 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 Pathology and NYU Cancer Center, New York University School of Medicine, New York, NY 10016, USA. Electronic address: ggi9001@med.cornell.edu.
    Abstract

    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.


    Copyright © 2015 Elsevier Inc. All rights reserved.

    Publikations ID: 25873174
    Quelle: öffnen
     
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