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

Date
2015
Authors
Küçük, C.
Jiang, B.
Hu X.
Zhang W.
Chan J.K.C.
Xiao W.
Lack, N.
Alkan, C.
Williams J.C.
Avery, K.N.
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Source Title
Nature Communications
Print ISSN
20411723
Electronic ISSN
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Nature Publishing Group
Volume
6
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Language
English
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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. © 2015 Macmillan Publishers Limited. All rights reserved.

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