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Cancer Cell. 2015 Apr 13;27(4):516-32. doi: 10.1016/j.ccell.2015.03.006.

Convergent mutations and kinase fusions lead to oncogenic STAT3 activation in anaplastic large cell lymphoma.

Author information

1
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.
2
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.
3
Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies, University of Torino, 10126 Torino, Italy.
4
Department of Control and Computer Engineering, Politecnico di Torino, 10129 Torino, Italy.
5
Department of Pathology, A.O. Città della Salute e della Scienza (Molinette), 10126 Torino, Italy.
6
Lymphoma and Genomics Research Program, Institute of Oncology Research, 6500 Bellinzona, Switzerland.
7
Translational Cell and Tissue Research Lab, KU Leuven, 3000 Leuven, Belgium.
8
Institute of Pathology, University of Würzburg and Comprehensive Cancer Center Mainfranken, 97080 Würzburg, Germany.
9
Ludwing Boltzmann Institute for Cancer Research, 1090 Vienna, Austria.
10
Research Unit Dermatopathology of the Medical University of Graz, 8036 Graz, Austria.
11
Institute of Pathology, University Hospital Basel, 4031 Basel, Switzerland.
12
Pathology & Lymphoid Malignancies Units, San Raffaele Scientific Institute, 20132 Milan, Italy.
13
Department of Human Pathology, University of Pavia and Scientific Institute Fondazione Policlinico San Matteo, 27100 Pavia, Italy.
14
Department of Pathology, City of Hope Medical Center, Duarte, CA 91010, USA.
15
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
16
Cancer Genomics, Instituto de Formación e Investigación Marqués de Valdecilla and Department of Pathology, Hospital Universitario Marqués de Valdecilla, 39008 Santander, Spain.
17
Department of Pathology and Diagnostics, University of Verona, 37134 Verona, Italy.
18
Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, 28100 Novara, Italy.
19
European Institute of Oncology, 20141 Milano, Italy; Bologna University School of Medicine, 40126 Bologna, Italy.
20
Institute of Hematology-Centro di Ricerche Onco-Ematologiche (CREO), Ospedale S. Maria della Misericordia, University of Perugia, 06100 Perugia, Italy.
21
The Jackson Laboratory, Bar Harbor, ME 04609, USA.
22
Janssen Research & Development, a Division of Janssen-Cilag, Campus de Maigremont, CS10615, 27106 Val-de-Reuil Cedex, France.
23
Janssen Research & Development, a Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium.
24
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.
25
Lymphoma and Genomics Research Program, Institute of Oncology Research, 6500 Bellinzona, Switzerland; Oncology Institute of Southern Switzerland, 6500 Bellinzona, Switzerland.
26
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.
27
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.

Erratum in

  • Cancer Cell. 2015 May 11;27(5):744.

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.

PMID:
25873174
PMCID:
PMC5898430
DOI:
10.1016/j.ccell.2015.03.006
[Indexed for MEDLINE]
Free PMC Article

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