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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 Gaul, 2015. "Activating mutations of STAT5B and STAT3 in lymphomas derived from γδ-T or NK cells," Nature Communications, Nature, vol. 6(1), pages 1-12, May.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7025
    DOI: 10.1038/ncomms7025
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