STAT3 and STAT5B Mutations in T/NK-Cell Chronic Lymphoproliferative Disorders of Large Granular Lymphocytes (LGL): Association with Disease Features

SIMPLE SUMMARY: STAT3 and STAT5B mutations have been identified in a subset of T and NK large granular lymphocytic leukemia (T/NK-LGLL). The aim of our study was to evaluate the frequency and type of these mutations in all different subtypes of T/NK-LGL expansions (n = 100 patients), as well as to analyze its association with biological and clinical features of the disease. We show for the first time that STAT3/5B mutations were present in all different T/NK-cell LGLL categories here studied; further, STAT3 mutations were associated with overall reduced counts of almost all normal residual populations of immune cells in blood, together with a shorter time-to-therapy vs. wild type T/NK-LGLL. These findings contribute to support the utility of the STAT3 mutation analysis for diagnostic and prognostic purposes in LGLL. ABSTRACT: STAT3 and STAT5B (STAT3/STAT5B) mutations are the most common mutations in T-cell large granular lymphocytic leukemia (T-LGLL) and chronic lymphoproliferative disorders of NK cells (CLPD-NK), but their clinical impact remains unknown. We investigated the frequency and type of STAT3/STAT5B mutations in FACS-sorted populations of expanded T/NK-LGL from 100 (82 clonal; 6 oligoclonal; 12 polyclonal) patients, and its relationship with disease features. Seventeen non-LGL T-CLPD patients and 628 age-matched healthy donors were analyzed as controls. STAT3 (n = 30) and STAT5B (n = 1) mutations were detected in 28/82 clonal T/NK-LGLL patients (34%), while absent (0/18, 0%) among oligoclonal/polyclonal LGL-lymphocytosis. Mutations were found across all diagnostic subgroups: TCD8(+)-LGLL, 36%; CLPD-NK, 38%; TCD4(+)-LGLL, 7%; Tαβ(+)DP-LGLL, 100%; Tαβ(+)DN-LGLL, 50%; Tγδ(+)-LGLL, 44%. STAT3-mutated T-LGLL/CLPD-NK showed overall reduced (p < 0.05) blood counts of most normal leukocyte subsets, with a higher rate (vs. nonmutated LGLL) of neutropenia (p = 0.04), severe neutropenia (p = 0.02), and cases requiring treatment (p = 0.0001), together with a shorter time-to-therapy (p = 0.0001), particularly in non-Y640F STAT3-mutated patients. These findings confirm and extend on previous observations about the high prevalence of STAT3 mutations across different subtypes of LGLL, and its association with a more marked decrease of all major blood-cell subsets and a shortened time-to-therapy.