Somatic STAT3 Mutations in Large Granular Lymphocytic Leukemia
Menée sur 77 patients atteints d'une forme rare de leucémie lymphocytaire T, cette étude identifie la présence fréquente de mutations du gène STAT3
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.) Supported by a special subsidy for health sciences, research, and training provided by the Finnish government and by grants from the Academy of Finland, the Finnish Cancer Societies, the Sigrid Juselius Foundation, the Finnish Association of Hematology, the National Clinical Graduate School, the Finnish Funding Agency for Technology and Innovation, the European Regional Development Fund, the Jane and Aatos Erkko Foundation, the K.A. Johansson Foundation, and the Signe and Ane Gyllenberg Foundation, and by grants from the National Institutes of Health (R01 CA127264A, to Mr. Clemente; R01AI085578, to Ms. Guinta; CA98472, to Dr. Loughran; and 2K24HL077522, to Dr. Maciejewski)