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

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. Herein, we aimed to study whether these mutations can also be detected in Felty syndrome, which would imply the existence of 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 ten 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 they are in large granular lymphocyte leukemia. Considering that the symptoms and treatment modalities are also similar, a unified reclassification of these two syndromes is warranted.

Vitamin D pathway activation selectively deactivates signal transducer and activator of transcription (STAT) proteins and inflammatory cytokine production in natural killer leukemic large granular lymphocytes

“…From the overlapping cytokines, we found some potential biomarkers to pursue. Several studies found IL-6 and/or TRAIL were elevated in TLGLL serum/plasma samples [40, 50, 51, 54], which we also observed in the NK-LGLL patients in this study. Interestingly, all three T-LGLL studies showed IL-8 was significantly elevated in T-LGLL compared to normal donors.…”

“…BCA-1/CXCL13, EOTAXIN-2/CCL24, IP-10/CXCL10, MIG/CXCL9, MIP-3β/CCL19, MIP-1β/CCL4, SDF-1α/β/CXCL12, and XCL/Lymphotactin are all classified as chemokines with their typical function being recruitment of leukocytes [11]. Recent work by our lab and collaborators found IP-10/CXCL10 was elevated in T-LGLL vs. normal controls [50]. G-CSF/CSF-3 and GM-CSF are colony stimulating factors that typically target stem cells in the bone marrow for the purpose of granulocyte production [11].…”

“…In this current study, we quantified serum levels of cytokines measured in previous T-LGLL studies [40, 50, 56], but we also assayed additional cytokines that were not considered in the past. This provided a basis for comparison and the opportunity to identify potential future targets.…”

Large granular lymphocyte cells and immune dysregulation diseases – the chicken or the egg?

“…The current description of high LGL counts and STAT3 mutations in FS thus extends the spectrum of immune dysregulation disease conditions in which LGL cells are prominently associated (Figure 1). Notably, in their series, Savola et al found four FS cases that also showed celiac disease (CD), 4 which confirms earlier suggestions of links between LGL cells, STAT3 mutations, and CD. 13,14 The presumed common pathogenesis of LGL leukemia and immune dysregulations such as FS, CD, and bone marrow failure and related conditions (AA, hypoplastic MDS, PNH) would pave the way for more sophisticated treatment strategies than the current general immune suppressive modalities which are frequently applied.…”

“…In this issue of Haematologica they report on a cohort of 14 FS patients, which were evaluated by next-generation sequencing (NGS) technology for the occurrence of somatic mutations in the STAT3 and STAT5B genes. 4 Both of these genes have been notably implicated in a subset of the CD8 + TCRαβ + T-cell type of LGL leukemia, and the occurrence of STAT3 mutations in LGL leukemia is strongly associated with RA and neutropenia. [5][6][7] Indeed, in >40% of FS cases somatic STAT3 hotspot mutations were found, which is at a rate comparable to LGL leukemia cases.…”