title: Discovery of somatic STAT5b mutations in large granular lymphocytic leukemia.
abstract: Large granular lymphocytic (LGL) leukemia is characterized by clonal expansion of cytotoxic T cells or natural killer cells. Recently, somatic mutations in the signal transducer and activator of transcription 3 (STAT3) gene were discovered in 28% to 40% of LGL leukemia patients. By exome and transcriptome sequencing of 2 STAT3 mutation-negative LGL leukemia patients, we identified a recurrent, somatic missense mutation (Y665F) in the Src-like homology 2 domain of the STAT5b gene. Targeted amplicon sequencing of 211 LGL leukemia patients revealed 2 additional patients with STAT5b mutations (N642H), resulting in a total frequency of 2% (4 of 211) of STAT5b mutations across all patients. The Y665F and N642H mutant constructs increased the transcriptional activity of STAT5 and tyrosine (Y694) phosphorylation, which was also observed in patient samples. The clinical course of the disease in patients with the N642H mutation was aggressive and fatal, clearly different from typical LGL leukemia with a relatively favorable outcome. This is the first time somatic STAT5 mutations are discovered in human cancer and further emphasizes the role of STAT family genes in the pathogenesis of LGL leukemia.
authors.affiliation: Hematology Research Unit Helsinki, Department of Medicine, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Hanna L M
authors.initials: HL
authors.lastname: Rajala
authors.forename: Samuli
authors.initials: S
authors.lastname: Eldfors
authors.forename: Heikki
authors.initials: H
authors.lastname: Kuusanmäki
authors.forename: Arjan J
authors.initials: AJ
authors.lastname: van Adrichem
authors.forename: Thomas
authors.initials: T
authors.lastname: Olson
authors.forename: Sonja
authors.initials: S
authors.lastname: Lagström
authors.forename: Emma I
authors.initials: EI
authors.lastname: Andersson
authors.forename: Andres
authors.initials: A
authors.lastname: Jerez
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Clemente
authors.forename: Yiyi
authors.initials: Y
authors.lastname: Yan
authors.forename: Dan
authors.initials: D
authors.lastname: Zhang
authors.forename: Andy
authors.initials: A
authors.lastname: Awwad
authors.forename: Pekka
authors.initials: P
authors.lastname: Ellonen
authors.forename: Olli
authors.initials: O
authors.lastname: Kallioniemi
authors.forename: Krister
authors.initials: K
authors.lastname: Wennerberg
authors.forename: Kimmo
authors.initials: K
authors.lastname: Porkka
authors.forename: Jaroslaw P
authors.initials: JP
authors.lastname: Maciejewski
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Loughran
authors.forename: Caroline
authors.initials: C
authors.lastname: Heckman
authors.forename: Satu
authors.initials: S
authors.lastname: Mustjoki
mesh_terms: D000368:Aged; D015331:Cohort Studies; D019281:Dimerization; D059472:Exome / Q000235:genetics; D005260:Female; D005820:Genetic Testing; D006367:HeLa Cells; D006801:Humans; D054066:Leukemia, Large Granular Lymphocytic / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016296:Mutagenesis; D009154:Mutation; D010766:Phosphorylation / Q000235:genetics; D017434:Protein Structure, Tertiary; D050799:STAT5 Transcription Factor / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics; D018909:src Homology Domains / Q000235:genetics*
chemical_list: D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; C494095:STAT5B protein, human; D025521:Tumor Suppressor Proteins