Journal
CANCER CELL
Volume 27, Issue 4, Pages 516-532Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2015.03.006
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Funding
- Italian Association for Cancer Research [10007]
- Regione Piemonte (ONCOPROT) [CIPE 25/2005]
- ImmOnc [BIO F.E.S.R. 2007/13]
- Oncology Program of Compagnia di San Paolo
- Torino
- Ricerca Finalizzata, Ministero della Salute
- AIRC [IG-13358]
- Compagnia di San Paolo [TO_Call2_2012_0061]
- NIH Cancer Core grant [CA034196]
- National Institutes of Health [R01 CA185486, R01 CA179044, U54 CA121852]
- Stewart Foundation
- Oncosuisse [KLS-02403-02-2009]
- Anna Lisa Stiftung
- Nelia and Amadeo Barletta Foundation
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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 similar to 20% of 155 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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