title: Convergent mutations and kinase fusions lead to oncogenic STAT3 activation in anaplastic large cell lymphoma.
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.
authors: 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.
authors: Ramona
authors: R
authors: Crescenzo
authors: 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.
authors: Francesco
authors: F
authors: Abate
authors: Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies, University of Torino, 10126 Torino, Italy.
authors: Elena
authors: E
authors: Lasorsa
authors: 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.
authors: Fabrizio
authors: F
authors: Tabbo'
authors: 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.
authors: Marcello
authors: M
authors: Gaudiano
authors: Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies, University of Torino, 10126 Torino, Italy.
authors: Nicoletta
authors: N
authors: Chiesa
authors: Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies, University of Torino, 10126 Torino, Italy.
authors: Filomena
authors: F
authors: Di Giacomo
authors: Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies, University of Torino, 10126 Torino, Italy.
authors: Elisa
authors: E
authors: Spaccarotella
authors: Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies, University of Torino, 10126 Torino, Italy.
authors: Luigi
authors: L
authors: Barbarossa
authors: Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies, University of Torino, 10126 Torino, Italy.
authors: Elisabetta
authors: E
authors: Ercole
authors: 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.
authors: Maria
authors: M
authors: Todaro
authors: 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.
authors: Michela
authors: M
authors: Boi
authors: Department of Control and Computer Engineering, Politecnico di Torino, 10129 Torino, Italy.
authors: Andrea
authors: A
authors: Acquaviva
authors: Department of Control and Computer Engineering, Politecnico di Torino, 10129 Torino, Italy.
authors: Elisa
authors: E
authors: Ficarra
authors: Department of Pathology, A.O. Città della Salute e della Scienza (Molinette), 10126 Torino, Italy.
authors: Domenico
authors: D
authors: Novero
authors: Lymphoma and Genomics Research Program, Institute of Oncology Research, 6500 Bellinzona, Switzerland.
authors: Andrea
authors: A
authors: Rinaldi
authors: Translational Cell and Tissue Research Lab, KU Leuven, 3000 Leuven, Belgium.
authors: Thomas
authors: T
authors: Tousseyn
authors: Institute of Pathology, University of Würzburg and Comprehensive Cancer Center Mainfranken, 97080 Würzburg, Germany.
authors: Andreas
authors: A
authors: Rosenwald
authors: Ludwing Boltzmann Institute for Cancer Research, 1090 Vienna, Austria.
authors: Lukas
authors: L
authors: Kenner
authors: Research Unit Dermatopathology of the Medical University of Graz, 8036 Graz, Austria.
authors: Lorenzo
authors: L
authors: Cerroni
authors: Institute of Pathology, University Hospital Basel, 4031 Basel, Switzerland.
authors: Alexander
authors: A
authors: Tzankov
authors: Pathology & Lymphoid Malignancies Units, San Raffaele Scientific Institute, 20132 Milan, Italy.
authors: Maurilio
authors: M
authors: Ponzoni
authors: Department of Human Pathology, University of Pavia and Scientific Institute Fondazione Policlinico San Matteo, 27100 Pavia, Italy.
authors: Marco
authors: M
authors: Paulli
authors: Department of Pathology, City of Hope Medical Center, Duarte, CA 91010, USA.
authors: Dennis
authors: D
authors: Weisenburger
authors: Department of Pathology, City of Hope Medical Center, Duarte, CA 91010, USA.
authors: Wing C
authors: WC
authors: Chan
authors: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors: Javeed
authors: J
authors: Iqbal
authors: Cancer Genomics, Instituto de Formación e Investigación Marqués de Valdecilla and Department of Pathology, Hospital Universitario Marqués de Valdecilla, 39008 Santander, Spain.
authors: Miguel A
authors: MA
authors: Piris
authors: Department of Pathology and Diagnostics, University of Verona, 37134 Verona, Italy.
authors: Alberto
authors: A
authors: Zamo'
authors: Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, 28100 Novara, Italy.
authors: Carmela
authors: C
authors: Ciardullo
authors: Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, 28100 Novara, Italy.
authors: Davide
authors: D
authors: Rossi
authors: Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, 28100 Novara, Italy.
authors: Gianluca
authors: G
authors: Gaidano
authors: European Institute of Oncology, 20141 Milano, Italy; Bologna University School of Medicine, 40126 Bologna, Italy.
authors: Stefano
authors: S
authors: Pileri
authors: Institute of Hematology-Centro di Ricerche Onco-Ematologiche (CREO), Ospedale S. Maria della Misericordia, University of Perugia, 06100 Perugia, Italy.
authors: Enrico
authors: E
authors: Tiacci
authors: Institute of Hematology-Centro di Ricerche Onco-Ematologiche (CREO), Ospedale S. Maria della Misericordia, University of Perugia, 06100 Perugia, Italy.
authors: Brunangelo
authors: B
authors: Falini
authors: The Jackson Laboratory, Bar Harbor, ME 04609, USA.
authors: Leonard D
authors: LD
authors: Shultz
authors: Janssen Research & Development, a Division of Janssen-Cilag, Campus de Maigremont, CS10615, 27106 Val-de-Reuil Cedex, France.
authors: Laurence
authors: L
authors: Mevellec
authors: Janssen Research & Development, a Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium.
authors: Jorge E
authors: JE
authors: Vialard
authors: 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 NYU Cancer Center, New York University School of Medicine, New York, NY 10016, USA.
authors: Roberto
authors: R
authors: Piva
authors: Lymphoma and Genomics Research Program, Institute of Oncology Research, 6500 Bellinzona, Switzerland; Oncology Institute of Southern Switzerland, 6500 Bellinzona, Switzerland.
authors: Francesco
authors: F
authors: Bertoni
authors: Department 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.
authors: Raul
authors: R
authors: Rabadan
authors: 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 Pathology and NYU Cancer Center, New York University School of Medicine, New York, NY 10016, USA. Electronic address: ggi9001@med.cornell.edu.
authors: Giorgio
authors: G
authors: Inghirami
mesh_terms: D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D053613:Janus Kinase 1 / Q000235:genetics; D017728:Lymphoma, Large-Cell, Anaplastic / Q000235:genetics*; D051379:Mice; D050506:Mutant Chimeric Proteins / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D053634:TYK2 Kinase / Q000235:genetics
chemical_list: D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse; D050506:Mutant Chimeric Proteins; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; C483813:Ros1 protein, mouse; C507905:Jak1 protein, mouse; D053613:Janus Kinase 1; D053634:TYK2 Kinase; C499356:Tyk2 protein, mouse