RGD Reference Report - Somatic STAT3 mutations in large granular lymphocytic leukemia. - Rat Genome Database

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Somatic STAT3 mutations in large granular lymphocytic leukemia.

Authors: Koskela, HL  Eldfors, S  Ellonen, P  Van Adrichem, AJ  Kuusanmaki, H  Andersson, EI  Lagstrom, S  Clemente, MJ  Olson, T  Jalkanen, SE  Majumder, MM  Almusa, H  Edgren, H  Lepisto, M  Mattila, P  Guinta, K  Koistinen, P  Kuittinen, T  Penttinen, K  Parsons, A  Knowles, J  Saarela, J  Wennerberg, K  Kallioniemi, O  Porkka, K  Loughran TP, JR  Heckman, CA  Maciejewski, JP  Mustjoki, S 
Citation: Koskela HL, etal., N Engl J Med. 2012 May 17;366(20):1905-13.
RGD ID: 6892936
Pubmed: PMID:22591296   (View Abstract at PubMed)
PMCID: PMC3693860   (View Article at PubMed Central)
DOI: DOI:10.1056/NEJMoa1114885   (Journal Full-text)

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.).

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
neutropenia  ISOStat3 (Rattus norvegicus)6892936; 6892936associated with T-cell large granular lymphocyte leukemiaRGD 
neutropenia  IAGP 6892936associated with T-cell large granular lymphocyte leukemiaRGD 
rheumatoid arthritis  IAGP 6892936associated with T-cell large granular lymphocyte leukemiaRGD 
rheumatoid arthritis  ISOSTAT3 (Homo sapiens)6892936; 6892936associated with T-cell large granular lymphocyte leukemiaRGD 

Objects Annotated

Genes (Rattus norvegicus)
Stat3  (signal transducer and activator of transcription 3)

Genes (Mus musculus)
Stat3  (signal transducer and activator of transcription 3)

Genes (Homo sapiens)
STAT3  (signal transducer and activator of transcription 3)


Additional Information