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

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

Author information

1
Department of Pathology, City of Hope Medical Center, Duarte, California 91010, USA.
2
Department of Pathology, West China Hospital of Sichuan University, Chengdu 610041, China.
3
Department of Pathology, Queen Elizabeth Hospital, Hong Kong, China.
4
Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, Food and Drug Administration, Maryland 20993, USA.
5
Department of Pharmacology, Koc University, Istanbul 34450, Turkey.
6
Department of Computer Engineering, Bilkent University, Ankara 06800, Turkey.
7
Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, California 91010, USA.
8
Department of Computer Engineering, Boğaziçi University, İstanbul 34342, Turkey.
9
Département de Pathologie, Groupe Henri-Mondor Albert-Chenevier, Inserm U955, Université Paris Est, Créteil 94000, France.
10
Molecular Biology of Lymphoid Malignancies Section, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
11
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198-3135, USA.
12
Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska 68198-5805, USA.
13
Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100029, China.
14
Department of Hematology, Aarhus University Hospital, Aarhus 8000, Denmark.
15
Department of Oncology, Helsinki University Central Hospital, PO Box 180, Helsinki 00029, Finland.
16
Pathologie Clinique Institut, Universitaire de Pathologie rue du Bugnon 25, CH 1011 Lausanne, Switzerland.

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.

PMID:
25586472
DOI:
10.1038/ncomms7025
[Indexed for MEDLINE]

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