title: STAT3 mutations unify the pathogenesis of chronic lymphoproliferative disorders of NK cells and T-cell large granular lymphocyte leukemia.
abstract: Chronic lymphoproliferative disorders of natural killer cells (CLPD-NKs) and T-cell large granular lymphocytic leukemias (T-LGLs) are clonal lymphoproliferations arising from either natural killer cells or cytotoxic T lymphocytes (CTLs). We have investigated for distribution and functional significance of mutations in 50 CLPD-NKs and 120 T-LGL patients by direct sequencing, allele-specific PCR, and microarray analysis. STAT3 gene mutations are present in both T and NK diseases: approximately one-third of patients with each type of disorder convey these mutations. Mutations were found in exons 21 and 20, encoding the Src homology 2 domain. Patients with mutations are characterized by symptomatic disease (75%), history of multiple treatments, and a specific pattern of STAT3 activation and gene deregulation, including increased expression of genes activated by STAT3. Many of these features are also found in patients with wild-type STAT3, indicating that other mechanisms of STAT3 activation can be operative in these chronic lymphoproliferative disorders. Treatment with STAT3 inhibitors, both in wild-type and mutant cases, resulted in accelerated apoptosis. STAT3 mutations are frequent in large granular lymphocytes suggesting a similar molecular dysregulation in malignant chronic expansions of NK and CTL origin. STAT3 mutations may distinguish truly malignant lymphoproliferations involving T and NK cells from reactive expansions.
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Andres
authors.initials: A
authors.lastname: Jerez
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Clemente
authors.forename: Hideki
authors.initials: H
authors.lastname: Makishima
authors.forename: Hanna
authors.initials: H
authors.lastname: Koskela
authors.forename: Francis
authors.initials: F
authors.lastname: Leblanc
authors.forename: Kwok
authors.initials: K
authors.lastname: Peng Ng
authors.forename: Thomas
authors.initials: T
authors.lastname: Olson
authors.forename: Bartlomiej
authors.initials: B
authors.lastname: Przychodzen
authors.forename: Manuel
authors.initials: M
authors.lastname: Afable
authors.forename: Ines
authors.initials: I
authors.lastname: Gomez-Segui
authors.forename: Kathryn
authors.initials: K
authors.lastname: Guinta
authors.forename: Lisa
authors.initials: L
authors.lastname: Durkin
authors.forename: Eric D
authors.initials: ED
authors.lastname: Hsi
authors.forename: Kathy
authors.initials: K
authors.lastname: McGraw
authors.forename: Dan
authors.initials: D
authors.lastname: Zhang
authors.forename: Marcin W
authors.initials: MW
authors.lastname: Wlodarski
authors.forename: Kimmo
authors.initials: K
authors.lastname: Porkka
authors.forename: Mikkael A
authors.initials: MA
authors.lastname: Sekeres
authors.forename: Alan
authors.initials: A
authors.lastname: List
authors.forename: Satu
authors.initials: S
authors.lastname: Mustjoki
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Loughran
authors.forename: Jaroslaw P
authors.initials: JP
authors.lastname: Maciejewski
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D049109:Cell Proliferation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D007694:Killer Cells, Natural / Q000473:pathology*; D054066:Leukemia, Large Granular Lymphocytic / Q000235:genetics* / Q000473:pathology*; D008232:Lymphoproliferative Disorders / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics*; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism / Q000473:pathology; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human