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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 &lt; 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.

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