Activating mutations of STAT5B and STAT3 in lymphomas derived from γδ-T or NK cells

Can Küçük, Bei Jiang, Xiaozhou Hu, Wenyan Zhang, John K. C. Chan, Wenming Xiao, Nathan Lack, Can Alkan, John C. Williams, Kendra N. Avery, Pınar Kavak, Anna Scuto, Emel Sen, Philippe Gaulard, Lou Staudt, Javeed Iqbal, Weiwei Zhang, Adam Cornish, Qiang Gong, Qunpei Yang, Hong Sun, Francesco d’Amore, Sirpa Leppä, Weiping Liu, Kai Fu, Laurence de Leval, Timothy McKeithan and Wing C. Chan ()
Additional contact information
Can Küçük: City of Hope Medical Center
Bei Jiang: City of Hope Medical Center
Xiaozhou Hu: City of Hope Medical Center
Wenyan Zhang: West China Hospital of Sichuan University
John K. C. Chan: Queen Elizabeth Hospital
Wenming Xiao: National Center for Toxicological Research, Food and Drug Administration
Nathan Lack: Koc University
Can Alkan: Bilkent University
John C. Williams: Beckman Research Institute of City of Hope
Kendra N. Avery: Beckman Research Institute of City of Hope
Pınar Kavak: Boğaziçi University
Anna Scuto: City of Hope Medical Center
Emel Sen: Koc University
Philippe Gaulard: Groupe Henri-Mondor Albert-Chenevier, Inserm U955, Université Paris Est
Lou Staudt: Molecular Biology of Lymphoid Malignancies Section, Center for Cancer Research, National Cancer Institute
Javeed Iqbal: University of Nebraska Medical Center
Weiwei Zhang: University of Nebraska Medical Center
Adam Cornish: Cell Biology and Anatomy, University of Nebraska Medical Center
Qiang Gong: Beijing Institute of Genomics, Chinese Academy of Sciences
Qunpei Yang: West China Hospital of Sichuan University
Hong Sun: West China Hospital of Sichuan University
Francesco d’Amore: Aarhus University Hospital
Sirpa Leppä: Helsinki University Central Hospital
Weiping Liu: West China Hospital of Sichuan University
Kai Fu: West China Hospital of Sichuan University
Laurence de Leval: Pathologie Clinique Institut, Universitaire de Pathologie rue du Bugnon 25
Timothy McKeithan: City of Hope Medical Center
Wing C. Chan: City of Hope Medical Center

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: Abstract Lymphomas arising from NK or γδ-T cells are very aggressive diseases and little is known regarding their pathogenesis. Here we report frequent activating mutations of STAT3 and STAT5B in NK/T-cell lymphomas (n=51), γδ-T-cell lymphomas (n=43) and their cell lines (n=9) through next generation and/or Sanger sequencing. STAT5B N642H is particularly frequent in all forms of γδ-T-cell lymphomas. STAT3 and STAT5B mutations are associated with increased phosphorylated protein and a growth advantage to transduced cell lines or normal NK cells. Growth-promoting activity of the mutants can be partially inhibited by a JAK1/2 inhibitor. Molecular modelling and surface plasmon resonance measurements of the N642H mutant indicate a marked increase in binding affinity of the phosphotyrosine-Y699 with the mutant histidine. This is associated with the prolonged persistence of the mutant phosphoSTAT5B and marked increase of binding to target sites. Our findings suggest that JAK-STAT pathway inhibition may represent a therapeutic strategy.

Date: 2015
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DOI: 10.1038/ncomms7025

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