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Somatic STAT3 mutations in the Felty syndrome: an implication for a common pathogenesis with large granular lymphocyte leukemia.

Somatic STAT3 mutations in the Felty syndrome: an implication for a common pathogenesis with large granular lymphocyte leukemia.
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Savola P, Brück O, Olson T, Kelkka T, Kauppi MJ, Kovanen PE, Kytölä S, Sokka-Isler T, Loughran TP, Leirisalo-Repo M, Mustjoki S,


Savola P, Brück O, Olson T, Kelkka T, Kauppi MJ, Kovanen PE, Kytölä S, Sokka-Isler T, Loughran TP, Leirisalo-Repo M, Mustjoki S, (click to view)

Savola P, Brück O, Olson T, Kelkka T, Kauppi MJ, Kovanen PE, Kytölä S, Sokka-Isler T, Loughran TP, Leirisalo-Repo M, Mustjoki S,

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Haematologica 2017 12 07() pii haematol.2017.175729
Abstract

Felty syndrome is a rare disease defined by neutropenia, splenomegaly, and rheumatoid arthritis. Sometimes the differential diagnosis between Felty syndrome and large granular lymphocyte leukemia is problematic. Recently, somatic STAT3 and STAT5B mutations were discovered in 30-40% of patients with large granular lymphocyte leukemia. We now aimed to study whether these mutations can also be detected in Felty syndrome, which would imply for a common pathogenic mechanism between these two disease entities. We collected samples and clinical information from 14 Felty syndrome patients who were monitored at the rheumatology outpatient clinic for Felty syndrome. Somatic STAT3 mutations were discovered in 43% (6/14) of Felty syndrome patients with deep amplicon sequencing targeting all STAT3 exons. Mutations were located in the SH2 domain of STAT3 which is a known mutational hotspot. No STAT5B mutations were found. In blood smears, overrepresentation of large granular lymphocytes was observed, and in the majority of cases the CD8+ T-cell receptor repertoire was skewed when analyzed by flow cytometry. In bone marrow biopsies, an increased amount of phospho-STAT3 positive cells was discovered. Plasma cytokine profiling showed that 10 of the 92 assayed cytokines were elevated both in Felty syndrome and large granular lymphocyte leukemia, and three of these cytokines were also increased in patients with uncomplicated rheumatoid arthritis. In conclusion, somatic STAT3 mutations and STAT3 activation are as frequent in Felty syndrome as in large granular lymphocyte leukemia. Considering that the symptoms and treatment modalities are also similar, unified re-classification of these two syndromes is warranted.

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