STAT3 mutation impacts biological and clinical features of T-LGL leukemia

Abstract

STAT3 mutations have been described in 30-40% of T-large granular lymphocyte (T-LGL) leukemia patients, leading to STAT3 pathway activation. Considering the heterogeneity of the disease and the several immunophenotypes that LGL clone may express, the aim of this work was to evaluate whether STAT3 mutations might be associated with a distinctive LGL immunophenotype and/or might be indicative for specific clinical features.Our series of cases included a pilot cohort of 101 T-LGL leukemia patients (68 CD8+/CD4- and 33 CD4+/CD8±) from Padua Hematology Unit (Italy) and a validation cohort of additional 20 patients from Rennes Hematology Unit (France).Our results indicate that i) CD8+ T-LGL leukemia patients with CD16+/CD56- immunophenotype identify a subset of patients characterized by the presence of STAT3 mutations and neutropenia, ii) CD4+/CD8± T-LGL leukemia are devoid of STAT3 mutations but characterized by STAT5b mutations, and iii) a correlation exists between STAT3 activation and presence of Fas ligand, this molecule resulting highly expressed in CD8+/CD16+/CD56- patients. Experiments with stimulation and inhibition of STAT3 phosphorylation confirmed this relationship. In conclusion, our data show that T-LGL leukemia with specific molecular and phenotypic patterns is associated with discrete clinical features contributing to get insights into molecular bases accounting for the development of Fas ligand-mediated neutropenia.

Insights Into Genetic Landscape of Large Granular Lymphocyte Leukemia

“…Somatic STAT3 mutations are preferentially located in the Src homology 2 (SH2) domain of the gene, leading to an increase of the stability of STAT3 protein dimerization that results in an enhanced transcriptional activity of pro-survival proteins (13). STAT3 mutation is preferentially found in CD8+ T-LGLL (14) and some TCRγδ LGLL cases (15), its incidence among the entire cohort of T-LGLL ranging from 11 up to 75% based on different reports (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). Y640F and D661Y are the most frequent STAT3 genetic lesions, accounting for about 60% of the recognized mutations.…”

“…The remnant other less frequent mutations include both point mutations and insertion or deletions and are mostly found in SH2 domain (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26), although some missense substitutions were described in DNA-binding and coiled coil domains [(27); Figure 1]. All T-LGLL patients are characterized by STAT3 activation, that is the hallmark of every T-LGLL, but a higher amount of the phosphorylated protein has been observed in cases with STAT3 mutations (13,14,17). Functional studies revealed that even if in different locations, most of the reported mutations lead to a higher protein transcriptional activity and cytokine responsiveness (13,27).…”

“…Another member of STAT protein family has been reported to carry gain-of-function mutations, namely STAT5b. Initially discovered in only 2% of CD8+ T-LGLL, specifically found in the aggressive form of LGLL (28), STAT5b mutations were subsequently identified in 15-55% of CD4+ T-LGLL (14,15,29), and in 19% of TCRγδ LGLL (15). To date, genetic alterations discovered in STAT5b are all point mutations located in the SH2 and in the transactivation domain of the gene (Figure 1).…”

“…A significant correlation between the presence of STAT3 mutations and neutropenia/symptomatic disease has already been highlighted in several studies (13-16, 22, 25). We hypothesized that the mechanism accounting for neutropenia development involves high levels of STAT3 activation (14). More in detail, we recently demonstrated the presence of a STAT3-miR-146b-FasL axis in neutropenic T-LGLL patients, that, once triggered, leads to high production of Fas Ligand, which in turn is responsible of neutrophil apoptosis (51).…”

A high definition picture of somatic mutations in chronic lymphoproliferative disorder of natural killer cells

“…Evidence on the genomic landscape of T-LGLL pointed to a key role of somatic mutations within JAK/STAT (mostly in STAT3 and STAT5B genes) and Ras/MAPK pathways [3][4][5][6][7][8][9][10] . In ANKL and NKTCL, JAK2 and STAT3 mutations, lesions of epigenetic modifiers and tumor suppressors were detected [11][12][13] .…”