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: Ramona Crescenzo, Francesco Abate, Elena Lasorsa, Fabrizio Tabbo', Marcello Gaudiano, Nicoletta Chiesa, Filomena Di Giacomo, Elisa Spaccarotella, Luigi Barbarossa, Elisabetta Ercole, Maria Todaro, Michela Boi, Andrea Acquaviva, Elisa Ficarra, Domenico Novero, Andrea Rinaldi, Thomas Tousseyn, Andreas Rosenwald, Lukas Kenner, Lorenzo Cerroni, Alexander Tzankov, Maurilio Ponzoni, Marco Paulli, Dennis Weisenburger, Wing C Chan, Javeed Iqbal, Miguel A Piris, Alberto Zamo', Carmela Ciardullo, Davide Rossi, Gianluca Gaidano, Stefano Pileri, Enrico Tiacci, Brunangelo Falini, Leonard D Shultz, Laurence Mevellec, Jorge E Vialard, Roberto Piva, Francesco Bertoni, Raul Rabadan, Giorgio Inghirami, European T-Cell Lymphoma Study Group, T-Cell Project: Prospective Collection of Data in Patients with Peripheral T-Cell Lymphoma and the AIRC 5xMille Consortium “Genetics-Driven Targeted Management of Lymphoid Malignancies”
• Journal: Cancer cell (Cancer Cell) Vol. 27 Issue 4 Pg. 516-32 (Apr 13 2015) ISSN: 1878-3686 [Electronic] United States
• PMID: 25873174 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Activating Transcription Factor 3
• Atf3 protein, mouse
• Mutant Chimeric Proteins
• NF-kappa B
• Proto-Oncogene Proteins
• STAT3 Transcription Factor
• Stat3 protein, mouse
• Receptor Protein-Tyrosine Kinases
• Ros1 protein, mouse
• Jak1 protein, mouse
• Janus Kinase 1
• TYK2 Kinase
• Tyk2 protein, mouse

Topics

• Activating Transcription Factor 3 (genetics, metabolism)
• Animals
• Cell Line, Tumor
• Gene Expression Regulation, Neoplastic
• HEK293 Cells
• Humans
• Janus Kinase 1 (genetics)
• Lymphoma, Large-Cell, Anaplastic (genetics)
• Mice
• Mutant Chimeric Proteins (genetics, metabolism)
• NF-kappa B (genetics)
• Phosphorylation
• Proto-Oncogene Proteins (genetics)
• Receptor Protein-Tyrosine Kinases (genetics)
• STAT3 Transcription Factor (genetics, metabolism)
• Signal Transduction
• TYK2 Kinase (genetics)