title: Activating mutations of STAT5B and STAT3 in lymphomas derived from γδ-T or NK cells.
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.
authors.affiliation: Department of Pathology, City of Hope Medical Center, Duarte, California 91010, USA.
authors.forename: Can
authors.initials: C
authors.lastname: Küçük
authors.affiliation: Department of Pathology, City of Hope Medical Center, Duarte, California 91010, USA.
authors.forename: Bei
authors.initials: B
authors.lastname: Jiang
authors.affiliation: Department of Pathology, City of Hope Medical Center, Duarte, California 91010, USA.
authors.forename: Xiaozhou
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Pathology, West China Hospital of Sichuan University, Chengdu 610041, China.
authors.forename: Wenyan
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Queen Elizabeth Hospital, Hong Kong, China.
authors.forename: John K C
authors.initials: JK
authors.lastname: Chan
authors.affiliation: Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, Food and Drug Administration, Maryland 20993, USA.
authors.forename: Wenming
authors.initials: W
authors.lastname: Xiao
authors.affiliation: Department of Pharmacology, Koc University, Istanbul 34450, Turkey.
authors.forename: Nathan
authors.initials: N
authors.lastname: Lack
authors.affiliation: Department of Computer Engineering, Bilkent University, Ankara 06800, Turkey.
authors.forename: Can
authors.initials: C
authors.lastname: Alkan
authors.affiliation: Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, California 91010, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Williams
authors.affiliation: Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, California 91010, USA.
authors.forename: Kendra N
authors.initials: KN
authors.lastname: Avery
authors.affiliation: Department of Computer Engineering, Boğaziçi University, İstanbul 34342, Turkey.
authors.forename: Pınar
authors.initials: P
authors.lastname: Kavak
authors.affiliation: Department of Pathology, City of Hope Medical Center, Duarte, California 91010, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Scuto
authors.affiliation: Department of Pharmacology, Koc University, Istanbul 34450, Turkey.
authors.forename: Emel
authors.initials: E
authors.lastname: Sen
authors.affiliation: Département de Pathologie, Groupe Henri-Mondor Albert-Chenevier, Inserm U955, Université Paris Est, Créteil 94000, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Gaulard
authors.affiliation: Molecular Biology of Lymphoid Malignancies Section, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
authors.forename: Lou
authors.initials: L
authors.lastname: Staudt
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198-3135, USA.
authors.forename: Javeed
authors.initials: J
authors.lastname: Iqbal
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198-3135, USA.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska 68198-5805, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Cornish
authors.affiliation: Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100029, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Gong
authors.affiliation: Department of Pathology, West China Hospital of Sichuan University, Chengdu 610041, China.
authors.forename: Qunpei
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Department of Pathology, West China Hospital of Sichuan University, Chengdu 610041, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Hematology, Aarhus University Hospital, Aarhus 8000, Denmark.
authors.forename: Francesco
authors.initials: F
authors.lastname: d'Amore
authors.affiliation: Department of Oncology, Helsinki University Central Hospital, PO Box 180, Helsinki 00029, Finland.
authors.forename: Sirpa
authors.initials: S
authors.lastname: Leppä
authors.affiliation: Department of Pathology, West China Hospital of Sichuan University, Chengdu 610041, China.
authors.forename: Weiping
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Pathology, West China Hospital of Sichuan University, Chengdu 610041, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Fu
authors.affiliation: Pathologie Clinique Institut, Universitaire de Pathologie rue du Bugnon 25, CH 1011 Lausanne, Switzerland.
authors.forename: Laurence
authors.initials: L
authors.lastname: de Leval
authors.affiliation: Department of Pathology, City of Hope Medical Center, Duarte, California 91010, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: McKeithan
authors.affiliation: Department of Pathology, City of Hope Medical Center, Duarte, California 91010, USA.
authors.forename: Wing C
authors.initials: WC
authors.lastname: Chan
mesh_terms: D001665:Binding Sites; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006639:Histidine / Q000737:chemistry; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D053613:Janus Kinase 1 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000166:cytology*; D016399:Lymphoma, T-Cell / Q000378:metabolism*; D009154:Mutation; D019000:Phosphotyrosine / Q000737:chemistry; D017434:Protein Structure, Tertiary; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics*; D050799:STAT5 Transcription Factor / Q000235:genetics*; D016176:T-Lymphocyte Subsets / Q000166:cytology*
chemical_list: C508594:IL2 protein, human; D007376:Interleukin-2; D016692:Receptors, Antigen, T-Cell, gamma-delta; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; C494095:STAT5B protein, human; D019000:Phosphotyrosine; D006639:Histidine; C507904:JAK1 protein, human; D053613:Janus Kinase 1