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

Nat Commun. 2015 Jan 14:6:6025. doi: 10.1038/ncomms7025.


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.

MeSH terms

  • Binding Sites
  • Gene Expression Regulation, Neoplastic*
  • HEK293 Cells
  • Histidine / chemistry
  • Humans
  • Interleukin-2 / metabolism
  • Janus Kinase 1 / metabolism
  • Killer Cells, Natural / cytology*
  • Lymphoma, T-Cell / metabolism*
  • Mutation
  • Phosphotyrosine / chemistry
  • Protein Structure, Tertiary
  • Receptors, Antigen, T-Cell, gamma-delta / metabolism
  • STAT3 Transcription Factor / genetics*
  • STAT5 Transcription Factor / genetics*
  • T-Lymphocyte Subsets / cytology*


  • IL2 protein, human
  • Interleukin-2
  • Receptors, Antigen, T-Cell, gamma-delta
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • STAT5 Transcription Factor
  • STAT5B protein, human
  • Phosphotyrosine
  • Histidine
  • JAK1 protein, human
  • Janus Kinase 1

Associated data

  • SRA/SRA200820