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.

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

CRESCENZO, RAMONA;TABBO', FABRIZIO;CHIESA, Nicoletta;DI GIACOMO, FILOMENA;TODARO, MARIA;ACQUAVIVA, ANDREA;Zamo', Alberto;PIVA, Roberto;INGHIRAMI, Giorgio
2015

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.
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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5898430/
Activating Transcription Factor 3; Animals; Cell Line, Tumor; HEK293 Cells; Humans; Janus Kinase 1; Lymphoma, Large-Cell, Anaplastic; Mice; Mutant Chimeric Proteins; NF-kappa B; Phosphorylation; Proto-Oncogene Proteins; Receptor Protein-Tyrosine Kinases; STAT3 Transcription Factor; Signal Transduction; TYK2 Kinase; Gene Expression Regulation, Neoplastic; Cancer Research; Cell Biology; Oncology; Medicine (all)
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
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1532759
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