TY - JOUR
T1 - Convergent mutations and kinase fusions lead to oncogenic STAT3 activation in anaplastic large cell lymphoma
AU - The 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
AU - Crescenzo, Ramona
AU - Abate, Francesco
AU - Lasorsa, Elena
AU - Tabbo', Fabrizio
AU - Gaudiano, Marcello
AU - Chiesa, Nicoletta
AU - Di Giacomo, Filomena
AU - Spaccarotella, Elisa
AU - Barbarossa, Luigi
AU - Ercole, Elisabetta
AU - Todaro, Maria
AU - Boi, Michela
AU - Acquaviva, Andrea
AU - Ficarra, Elisa
AU - Novero, Domenico
AU - Rinaldi, Andrea
AU - Tousseyn, Thomas
AU - Rosenwald, Andreas
AU - Kenner, Lukas
AU - Cerroni, Lorenzo
AU - Tzankov, Alexander
AU - Ponzoni, Maurilio
AU - Paulli, Marco
AU - Weisenburger, Dennis
AU - Chan, Wing C.
AU - Iqbal, Javeed
AU - Piris, Miguel A.
AU - Zamo', Alberto
AU - Ciardullo, Carmela
AU - Rossi, Davide
AU - Gaidano, Gianluca
AU - Pileri, Stefano
AU - Tiacci, Enrico
AU - Falini, Brunangelo
AU - Shultz, Leonard D.
AU - Mevellec, Laurence
AU - Vialard, Jorge E.
AU - Piva, Roberto
AU - Bertoni, Francesco
AU - Rabadan, Raul
AU - Inghirami, Giorgio
N1 - Funding Information:
We thank Drs. L. Cerchietti, J. Wang, H. Khiabanian, and P. Kyriakides for discussion and suggestions on the manuscript. We are grateful to S.A. Fasteris and the Epigenomics Core Facility of Weill Cornell Medical College for their technical support. We are grateful to Drs. B. Ruggeri and W. Chan (ALK inhibitors); V. Poli, F. Bussolino, and A. Bardelli (cell lines); R. Doebele (ROS1 fusion); R. Dalla Favera (Lyt10 and IgK-HIV-kB); and J. Bromberg (dominant-negative STAT3) for their reagents. We would like to thank Drs. Olivier Elemento, Neel S. Madhukar, and Peter L. Nagy, for their support in the bioinformatics analyses. We also thank E. Mereu for her technical support. We show gratitude to the technical staff of the Immunopathology Laboratory at Weill Cornell Medical College. G.I. is supported by the Italian Association for Cancer Research (5x1000 No. 10007); Regione Piemonte (ONCOPROT, CIPE 25/2005); and ImmOnc (BIO F.E.S.R. 2007/13), the Oncology Program of Compagnia di San Paolo, Torino, and Ricerca Finalizzata, Ministero della Salute. R.P. is supported by AIRC (IG-13358) and Compagnia di San Paolo (TO_Call2_2012_0061). L.D.S. is supported by NIH Cancer Core grant CA034196. R.R. is supported by National Institutes of Health grants R01 CA185486, R01 CA179044, and U54 CA121852 and the Stewart Foundation. F.B. is supported by Oncosuisse KLS-02403-02-2009, Anna Lisa Stiftung, and the Nelia and Amadeo Barletta Foundation.
Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015/4/13
Y1 - 2015/4/13
N2 - 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 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 invitro and invivo.
AB - 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 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 invitro and invivo.
UR - http://www.scopus.com/inward/record.url?scp=84928015700&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84928015700&partnerID=8YFLogxK
U2 - 10.1016/j.ccell.2015.03.006
DO - 10.1016/j.ccell.2015.03.006
M3 - Article
C2 - 25873174
AN - SCOPUS:84928015700
SN - 1535-6108
VL - 27
SP - 516
EP - 532
JO - Cancer Cell
JF - Cancer Cell
IS - 4
ER -