TY - JOUR

T1 - Somatic STAT3 mutations in large granular lymphocytic leukemia

AU - Koskela, Hanna L M

AU - Eldfors, Samuli

AU - Ellonen, Pekka

AU - van Adrichem, Arjan J

AU - Kuusanmäki, Heikki

AU - Andersson, Emma I

AU - Lagström, Sonja

AU - Clemente, Michael J

AU - Olson, Thomas

AU - Jalkanen, Sari E

AU - Majumder, Muntasir Mamun

AU - Almusa, Henrikki

AU - Edgren, Henrik

AU - Lepistö, Maija

AU - Mattila, Pirkko

AU - Guinta, Kathryn

AU - Koistinen, Pirjo

AU - Kuittinen, Taru

AU - Penttinen, Kati

AU - Parsons, Alun

AU - Knowles, Jonathan

AU - Saarela, Janna

AU - Wennerberg, Krister

AU - Kallioniemi, Olli

AU - Porkka, Kimmo

AU - Loughran, Thomas P

AU - Heckman, Caroline A

AU - Maciejewski, Jaroslaw P

AU - Mustjoki, Satu

PY - 2012/5/17

Y1 - 2012/5/17

N2 - 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.).

AB - 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.).

KW - Aged

KW - Exome

KW - Gene Expression

KW - Humans

KW - Leukemia, Large Granular Lymphocytic/genetics

KW - Male

KW - Mutation

KW - Receptors, Antigen, T-Cell

KW - STAT3 Transcription Factor/genetics

KW - Sequence Analysis, RNA

KW - Transcription, Genetic

KW - Up-Regulation

U2 - 10.1056/NEJMoa1114885

DO - 10.1056/NEJMoa1114885

M3 - Journal article

C2 - 22591296

VL - 366

SP - 1905

EP - 1913

JO - New England Journal of Medicine

JF - New England Journal of Medicine

SN - 0028-4793

IS - 20

ER -