Convergent Mutations and Kinase Fusions Lead to Oncogenic STAT3 Activation in Anaplastic Large Cell Lymphoma

被引：376

作者：

Crescenzo, Ramona ^{[1
,2
]}

Abate, Francesco ^{[1
,3
,4
,5
]}

Lasorsa, Elena ^{[1
]}

Tabbo', Fabrizio ^{[1
,2
]}

Gaudiano, Marcello ^{[1
,2
]}

Chiesa, Nicoletta ^{[1
]}

Di Giacomo, Filomena ^{[1
]}

Spaccarotella, Elisa ^{[1
]}

Barbarossa, Luigi ^{[1
]}

Ercole, Elisabetta ^{[1
]}

Todaro, Maria ^{[1
,2
]}

Boi, Michela ^{[1
,2
]}

Acquaviva, Andrea ^{[3
]}

Ficarra, Elisa ^{[3
]}

Novero, Domenico ^{[6
]}

Rinaldi, Andrea ^{[7
]}

Tousseyn, Thomas ^{[8
]}

Rosenwald, Andreas ^{[9
,10
]}

Kenner, Lukas ^{[11
]}

Cerroni, Lorenzo ^{[12
]}

Tzankov, Alexander ^{[13
]}

Ponzoni, Maurilio ^{[14
,15
]}

Paulli, Marco ^{[16
,17
]}

Weisenburger, Dennis ^{[18
]}

Chan, Wing C. ^{[18
]}

Iqbal, Javeed ^{[19
]}

Piris, Miguel A. ^{[20
,21
]}

Zamo', Alberto ^{[22
]}

Ciardullo, Carmela ^{[23
]}

Rossi, Davide ^{[23
]}

Gaidano, Gianluca ^{[23
]}

Pileri, Stefano ^{[24
,25
]}

Tiacci, Enrico ^{[26
]}

Falini, Brunangelo ^{[26
]}

Shultz, Leonard D. ^{[27
]}

Mevellec, Laurence ^{[28
]}

Vialard, Jorge E. ^{[29
]}

Piva, Roberto ^{[1
,30
,31
]}

Bertoni, Francesco ^{[7
,32
]}

Rabadan, Raul ^{[4
,5
]}

Inghirami, Giorgio ^{[1
,2
,30
,31
]}

机构：

[1] Univ Turin, Dept Mol Biotechnol & Hlth Sci, I-10126 Turin, Italy

[2] Weill Cornell Med Coll, Dept Pathol & Lab Med, New York, NY 10021 USA

[3] Politecn Torino, Dept Control & Comp Engn, I-10129 Turin, Italy

[4] Columbia Univ, Ctr Computat Biol & Bioinformat, Dept Biomed Informat, New York, NY 10027 USA

[5] Columbia Univ, Ctr Computat Biol & Bioinformat, Dept Syst Biol, New York, NY 10027 USA

[6] AO Citta Salute Sci Molinette, Dept Pathol, I-10126 Turin, Italy

[7] Oncol Res Inst, Lymphoma & Genom Res Program, CH-6500 Bellinzona, Switzerland

[8] Katholieke Univ Leuven, Translat Cell & Tissue Res Lab, B-3000 Leuven, Belgium

[9] Univ Wurzburg, Inst Pathol, D-97080 Wurzburg, Germany

[10] Comprehens Canc Ctr Mainfranken, D-97080 Wurzburg, Germany

[11] Ludwing Boltzmann Inst Canc Res, A-1090 Vienna, Austria

[12] Med Univ Graz, Res Unit Dermatopathol, A-8036 Graz, Austria

[13] Univ Basel Hosp, Inst Pathol, CH-4031 Basel, Switzerland

[14] Ist Sci San Raffaele, Pathol Unit, I-20132 Milan, Italy

[15] Ist Sci San Raffaele, Lymphoid Malignancies Unit, I-20132 Milan, Italy

[16] Univ Pavia, Dept Human Pathol, I-27100 Pavia, Italy

[17] Sci Inst Fdn Policlin San Matteo, I-27100 Pavia, Italy

[18] City Hope Natl Med Ctr, Dept Pathol, Duarte, CA 91010 USA

[19] Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Omaha, NE 68198 USA

[20] Inst Formac & Invest Marques de Valdecilla, Canc Genom, Santander 39008, Spain

[21] Hosp Univ Marques de Valdecilla, Dept Pathol, Santander 39008, Spain

[22] Univ Verona, Dept Pathol & Diagnost, I-37134 Verona, Italy

[23] Amedeo Avogadro Univ Eastern Piedmont, Dept Translat Med, Div Hematol, I-28100 Novara, Italy

[24] European Inst Oncol, I-20141 Milan, Italy

[25] Univ Bologna, Sch Med, I-40126 Bologna, Italy

[26] Univ Perugia, Osped S Maria della Misericordia, CREO, Inst Hematol, I-06100 Perugia, Italy

[27] Jackson Lab, Bar Harbor, ME 04609 USA

[28] Janssen Res & Dev, F-27106 Val De Reuil, France

[29] Janssen Res & Dev, B-2340 Beerse, Belgium

[30] NYU, Sch Med, Dept Pathol, New York, NY 10016 USA

[31] NYU, Sch Med, Ctr Canc, New York, NY 10016 USA

[32] Oncol Inst Southern Switzerland, CH-6500 Bellinzona, Switzerland

来源：

CANCER CELL | 2015年 / 27卷 / 04期

基金：

美国国家卫生研究院;

关键词：

PERIPHERAL T-CELL; GENE; LANDSCAPE; REVEALS; FREQUENT; DOMAINS; TYK2;

D O I：

10.1016/j.ccell.2015.03.006

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

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.

引用

页码：516 / 532

页数：17

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