Küçük, C.Jiang, B.Hu X.Zhang W.Chan J.K.C.Xiao W.Lack, N.Alkan, C.Williams J.C.Avery, K.N.Kavak P.Scuto, A.Sen, E.Gaulard P.Staudt L.Iqbal J.Zhang W.Cornish, A.Gong Q.Yang Q.Sun H.D'Amore F.Leppä, S.Liu W.Fu, K.De Leval L.McKeithan, T.Chan W.C.2016-02-082016-02-08201520411723http://hdl.handle.net/11693/23825Lymphomas 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. © 2015 Macmillan Publishers Limited. All rights reserved.EnglishhistidineJanus kinase 2 inhibitorJanus kinase inhibitormutant proteinphosphotyrosineSTAT5b proteindisease treatmentinhibitionmolecular analysismutationparthenogenesisproteintumorArticlebinding affinitybinding sitecancer growthcontrolled studygamma delta T lymphocytegene mutationhumanhuman celllymphoma cell linemeasurementmolecular modelmutator genenatural killer cellNK T cell lymphomaprotein phosphorylationSTAT3 geneSTAT5B genesurface plasmon resonanceT cell lymphomaArticle10.1038/ncomms7025