Somatic STAT3 Mutations in Large Granular Lymphocytic Leukemia
By H. Koskela, S. Eldfors, P. Ellonen, A. V. van Adrichem, H. Kuusanmäki, E. Andersson, S. Lagström, M. Clemente, T. Olson, S. Jalkanen and 19 more. New England Journal of Medicine, 2012
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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.)
Subfields: Genetics, Immunology, Pathology and Forensic Medicine
View Paper: https://www.semanticscholar.org/paper/c4a43aab025807a3c51fc82bb8a81df209f173e8
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Citations in the corpus
- The JAK-STAT Pathway: Impact on Human Disease and Therapeutic Intervention (2015, background): “Mutations of the SH2 domain of STAT3 are present in 40% of large granular leukemias (37).”
- The 2016 revision of the World Health Organization classification of lymphoid neoplasms. (2016, neutral): “STAT3 mutations are common in large granular lymphocyte leukemias of both T-cell andNK-cell types.(123,124) STAT5B mutations are more uncommon and are associated with more clinically aggressive disease.”
- JAK–STAT Signaling as a Target for Inflammatory and Autoimmune Diseases: Current and Future Prospects (2017, background): “Somatic STAT3 mutations are also associated with a broad range of hematologic and solid organ malignancies, which make STAT3 blockade an active area of research for therapeutic agents [56, 57].”