Advanced search
1 file | 2.53 MB

JAK3 deregulation by activating mutations confers invasive growth advantage in extranodal nasal-type natural killer cell lymphoma

(2014) LEUKEMIA. 28(2). p.338-348
Author
Organization
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.
Keywords
leukemia, natural killer lymphoma, JAK3, STAT3, ACUTE MEGAKARYOBLASTIC LEUKEMIA, TUMOR-SUPPRESSOR GENE, T-CELL, RHEUMATOID-ARTHRITIS, TRANSPLANTATION, CLASSIFICATION, IDENTIFICATION, TOFACITINIB, EXPRESSION, INHIBITOR

Downloads

  • (...).pdf
    • full text
    • |
    • UGent only
    • |
    • PDF
    • |
    • 2.53 MB

Citation

Please use this url to cite or link to this publication:

Chicago
Bouchekioua, A, L Scourzic, Olivier De Wever, Y Zhang, P Cervera, A Aline-Fardin, T Mercher, et al. 2014. “JAK3 Deregulation by Activating Mutations Confers Invasive Growth Advantage in Extranodal Nasal-type Natural Killer Cell Lymphoma.” Leukemia 28 (2): 338–348.
APA
Bouchekioua, A., Scourzic, L., De Wever, O., Zhang, Y., Cervera, P., Aline-Fardin, A., Mercher, T., et al. (2014). JAK3 deregulation by activating mutations confers invasive growth advantage in extranodal nasal-type natural killer cell lymphoma. LEUKEMIA, 28(2), 338–348.
Vancouver
1.
Bouchekioua A, Scourzic L, De Wever O, Zhang Y, Cervera P, Aline-Fardin A, et al. JAK3 deregulation by activating mutations confers invasive growth advantage in extranodal nasal-type natural killer cell lymphoma. LEUKEMIA. 2014;28(2):338–48.
MLA
Bouchekioua, A, L Scourzic, Olivier De Wever, et al. “JAK3 Deregulation by Activating Mutations Confers Invasive Growth Advantage in Extranodal Nasal-type Natural Killer Cell Lymphoma.” LEUKEMIA 28.2 (2014): 338–348. Print.
@article{4328980,
  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.},
  author       = {Bouchekioua, A and Scourzic, L and De Wever, Olivier and Zhang, Y and Cervera, P and Aline-Fardin, A and Mercher, T and Gaulard, P and Nyga, R and Jeziorowska, D and Douay, L and Vainchenker, W and Louache, F and Gespach, C and Solary, E and Coppo, P},
  issn         = {0887-6924},
  journal      = {LEUKEMIA},
  keyword      = {leukemia,natural killer lymphoma,JAK3,STAT3,ACUTE MEGAKARYOBLASTIC LEUKEMIA,TUMOR-SUPPRESSOR GENE,T-CELL,RHEUMATOID-ARTHRITIS,TRANSPLANTATION,CLASSIFICATION,IDENTIFICATION,TOFACITINIB,EXPRESSION,INHIBITOR},
  language     = {eng},
  number       = {2},
  pages        = {338--348},
  title        = {JAK3 deregulation by activating mutations confers invasive growth advantage in extranodal nasal-type natural killer cell lymphoma},
  url          = {http://dx.doi.org/10.1038/leu.2013.157},
  volume       = {28},
  year         = {2014},
}

Altmetric
View in Altmetric
Web of Science
Times cited: