title: Somatic STAT3 mutations in large granular lymphocytic leukemia.
abstract: BACKGROUND
  T-cell large granular lymphocytic leukemia is a rare lymphoproliferative disorder characterized by the expansion of clonal CD3+CD8+ cytotoxic T lymphocytes (CTLs) and often associated with autoimmune disorders and immune-mediated cytopenias.
  
  
  METHODS
  We used next-generation exome sequencing to identify somatic mutations in CTLs from an index patient with large granular lymphocytic leukemia. Targeted resequencing was performed in a well-characterized cohort of 76 patients with this disorder, characterized by clonal T-cell-receptor rearrangements and increased numbers of large granular lymphocytes.
  
  
  RESULTS
  Mutations in the signal transducer and activator of transcription 3 gene (STAT3) were found in 31 of 77 patients (40%) with large granular lymphocytic leukemia. Among these 31 patients, recurrent mutational hot spots included Y640F in 13 (17%), D661V in 7 (9%), D661Y in 7 (9%), and N647I in 3 (4%). All mutations were located in exon 21, encoding the Src homology 2 (SH2) domain, which mediates the dimerization and activation of STAT protein. The amino acid changes resulted in a more hydrophobic protein surface and were associated with phosphorylation of STAT3 and its localization in the nucleus. In vitro functional studies showed that the Y640F and D661V mutations increased the transcriptional activity of STAT3. In the affected patients, downstream target genes of the STAT3 pathway (IFNGR2, BCL2L1, and JAK2) were up-regulated. Patients with STAT3 mutations presented more often with neutropenia and rheumatoid arthritis than did patients without these mutations.
  
  
  CONCLUSIONS
  The SH2 dimerization and activation domain of STAT3 is frequently mutated in patients with large granular lymphocytic leukemia; these findings suggest that aberrant STAT3 signaling underlies the pathogenesis of this disease. (Funded by the Academy of Finland and others.).
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: Koskela
authors.forename: Samuli
authors.initials: S
authors.lastname: Eldfors
authors.forename: Pekka
authors.initials: P
authors.lastname: Ellonen
authors.forename: Arjan J
authors.initials: AJ
authors.lastname: van Adrichem
authors.forename: Heikki
authors.initials: H
authors.lastname: Kuusanmäki
authors.forename: Emma I
authors.initials: EI
authors.lastname: Andersson
authors.forename: Sonja
authors.initials: S
authors.lastname: Lagström
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Clemente
authors.forename: Thomas
authors.initials: T
authors.lastname: Olson
authors.forename: Sari E
authors.initials: SE
authors.lastname: Jalkanen
authors.forename: Muntasir Mamun
authors.initials: MM
authors.lastname: Majumder
authors.forename: Henrikki
authors.initials: H
authors.lastname: Almusa
authors.forename: Henrik
authors.initials: H
authors.lastname: Edgren
authors.forename: Maija
authors.initials: M
authors.lastname: Lepistö
authors.forename: Pirkko
authors.initials: P
authors.lastname: Mattila
authors.forename: Kathryn
authors.initials: K
authors.lastname: Guinta
authors.forename: Pirjo
authors.initials: P
authors.lastname: Koistinen
authors.forename: Taru
authors.initials: T
authors.lastname: Kuittinen
authors.forename: Kati
authors.initials: K
authors.lastname: Penttinen
authors.forename: Alun
authors.initials: A
authors.lastname: Parsons
authors.forename: Jonathan
authors.initials: J
authors.lastname: Knowles
authors.forename: Janna
authors.initials: J
authors.lastname: Saarela
authors.forename: Krister
authors.initials: K
authors.lastname: Wennerberg
authors.forename: Olli
authors.initials: O
authors.lastname: Kallioniemi
authors.forename: Kimmo
authors.initials: K
authors.lastname: Porkka
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Loughran
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Heckman
authors.forename: Jaroslaw P
authors.initials: JP
authors.lastname: Maciejewski
authors.forename: Satu
authors.initials: S
authors.lastname: Mustjoki
mesh_terms: D000368:Aged; D059472:Exome; D015870:Gene Expression; D006801:Humans; D054066:Leukemia, Large Granular Lymphocytic / Q000235:genetics*; D008297:Male; D009154:Mutation; D011948:Receptors, Antigen, T-Cell; D050796:STAT3 Transcription Factor / Q000235:genetics*; D017423:Sequence Analysis, RNA; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: D011948:Receptors, Antigen, T-Cell; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human