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

A Bouchekioua, L Scourzic, Olivier De Wever UGent, Y Zhang, P Cervera, A Aline-Fardin, T Mercher, P Gaulard, R Nyga, D Jeziorowska, et al. (2014) LEUKEMIA. 28(2). p.338-348
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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
leukemia, natural killer lymphoma, JAK3, STAT3, ACUTE MEGAKARYOBLASTIC LEUKEMIA, TUMOR-SUPPRESSOR GENE, T-CELL, RHEUMATOID-ARTHRITIS, TRANSPLANTATION, CLASSIFICATION, IDENTIFICATION, TOFACITINIB, EXPRESSION, INHIBITOR
journal title
LEUKEMIA
Leukemia
volume
28
issue
2
pages
338 - 348
Web of Science type
Article
Web of Science id
000331223900013
JCR category
ONCOLOGY
JCR impact factor
10.431 (2014)
JCR rank
9/211 (2014)
JCR quartile
1 (2014)
ISSN
0887-6924
DOI
10.1038/leu.2013.157
language
English
UGent publication?
yes
classification
A1
additional info
the authors LS, ODW, YZ, CG and ES contributed equally to this work
copyright statement
I have transferred the copyright for this publication to the publisher
id
4328980
handle
http://hdl.handle.net/1854/LU-4328980
date created
2014-03-11 15:07:02
date last changed
2016-12-19 15:43:22
@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},
}

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.