title: JAK3 deregulation by activating mutations confers invasive growth advantage in extranodal nasal-type natural killer cell lymphoma.
abstract: Extranodal, nasal-type natural killer (NK)/T-cell lymphoma (NKCL) is an aggressive malignancy with poor prognosis in which, usually, signal transducer and activator of transcription 3 (STAT3) is constitutively activated and oncogenic. Here, we demonstrate that STAT3 activation mostly results from constitutive Janus kinase (JAK)3 phosphorylation on tyrosine 980, as observed in three of the four tested NKCL cell lines and in 20 of the 23 NKCL tumor samples under study. In one of the cell lines and in 4 of 19 (21%) NKCL primary tumor samples, constitutive JAK3 activation was related to an acquired mutation (A573V or V722I) in the JAK3 pseudokinase domain. We then show that constitutive activation of the JAK3/STAT3 pathway has a major role in NKCL cell growth and survival and in the invasive phenotype. Indeed, NKCL cell growth was slowed down in vitro by targeting JAK3 with chemical inhibitors or small-interfering RNAs. In a human NKCL xenograft mouse model, tumor growth was significantly delayed by the JAK3 inhibitor CP-690550. Altogether, the constitutive activation of JAK3, which can result from JAK3-activating mutations, is a frequent feature of NKCL that deserves to be tested as a therapeutic target.
authors.affiliation: 1] Unité Inserm U1009 'Hématopoïèse normale et pathologique'; Institut Gustave Roussy, Villejuif, France [2] Université Paris 11, Institut Gustave Roussy, Villejuif, France [3] Institut Gustave Roussy, Villejuif, France [4] U938 'Cellules souches: application à la thérapie cellulaire hématopoïétique', Centre de Recherche Saint-Antoine, UPMC University Paris 06, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Bouchekioua
authors.affiliation: 1] Université Paris 11, Institut Gustave Roussy, Villejuif, France [2] Institut Gustave Roussy, Villejuif, France [3] Unité Inserm U985 'Génétique des tumeurs', Institut Gustave Roussy, Villejuif, France.
authors.forename: L
authors.initials: L
authors.lastname: Scourzic
authors.affiliation: Laboratory of Experimental Cancer Research, Department of Radiotherapy and Nuclear Medicine, Ghent University Hospital, Ghent, Belgium.
authors.forename: O
authors.initials: O
authors.lastname: de Wever
authors.affiliation: 1] Unité Inserm U1009 'Hématopoïèse normale et pathologique'; Institut Gustave Roussy, Villejuif, France [2] Université Paris 11, Institut Gustave Roussy, Villejuif, France [3] Institut Gustave Roussy, Villejuif, France.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Service d'Anatomo-pathologie, AP-HP, Hôpitaux Universitaires Paris-Est, UPMC University Paris 06, Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Cervera
authors.affiliation: Service d'Anatomo-pathologie, AP-HP, Hôpitaux Universitaires Paris-Est, UPMC University Paris 06, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Aline-Fardin
authors.affiliation: 1] Université Paris 11, Institut Gustave Roussy, Villejuif, France [2] Institut Gustave Roussy, Villejuif, France [3] Unité Inserm U985 'Génétique des tumeurs', Institut Gustave Roussy, Villejuif, France.
authors.forename: T
authors.initials: T
authors.lastname: Mercher
authors.affiliation: 1] Inserm U955, Créteil, France [2] Université Paris-Est, Créteil, France [3] Département de Pathologie, AP-HP, Hôpital Henri Mondor, Créteil, France.
authors.forename: P
authors.initials: P
authors.lastname: Gaulard
authors.affiliation: Service d'Immunologie, UFR de Médecine, 3 Rue des Louvels, Amiens, France.
authors.forename: R
authors.initials: R
authors.lastname: Nyga
authors.affiliation: U938 'Cellules souches: application à la thérapie cellulaire hématopoïétique', Centre de Recherche Saint-Antoine, UPMC University Paris 06, Paris, France.
authors.forename: D
authors.initials: D
authors.lastname: Jeziorowska
authors.affiliation: U938 'Cellules souches: application à la thérapie cellulaire hématopoïétique', Centre de Recherche Saint-Antoine, UPMC University Paris 06, Paris, France.
authors.forename: L
authors.initials: L
authors.lastname: Douay
authors.affiliation: 1] Unité Inserm U1009 'Hématopoïèse normale et pathologique'; Institut Gustave Roussy, Villejuif, France [2] Université Paris 11, Institut Gustave Roussy, Villejuif, France [3] Institut Gustave Roussy, Villejuif, France.
authors.forename: W
authors.initials: W
authors.lastname: Vainchenker
authors.affiliation: 1] Unité Inserm U1009 'Hématopoïèse normale et pathologique'; Institut Gustave Roussy, Villejuif, France [2] Université Paris 11, Institut Gustave Roussy, Villejuif, France [3] Institut Gustave Roussy, Villejuif, France.
authors.forename: F
authors.initials: F
authors.lastname: Louache
authors.affiliation: Unité Inserm U938 'Molecular and Clinical Oncology', UPMC University Paris 06.
authors.forename: C
authors.initials: C
authors.lastname: Gespach
authors.affiliation: 1] Unité Inserm U1009 'Hématopoïèse normale et pathologique'; Institut Gustave Roussy, Villejuif, France [2] Université Paris 11, Institut Gustave Roussy, Villejuif, France [3] Institut Gustave Roussy, Villejuif, France.
authors.forename: E
authors.initials: E
authors.lastname: Solary
authors.affiliation: 1] Unité Inserm U1009 'Hématopoïèse normale et pathologique'; Institut Gustave Roussy, Villejuif, France [2] Centre de Référence des Microangiopathies Thrombotiques, Service d'Hématologie, AP-HP, Hôpitaux Universitaires Paris-Est, UPMC University Paris 06, Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Coppo
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D054391:Lymphoma, Extranodal NK-T-Cell / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D010766:Phosphorylation; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; C479163:tofacitinib; D053616:Janus Kinase 3