![]() Panel B: Specific STAT3/5B Gene Mutations Identified in Purified Clonal T/NK-cell LGL Populations ( n = 31) from 28 T/NK-LGLL Patients Panel A: Distribution of STAT3 and STAT5B Gene Mutations in the LGLL Patients and Clonal T/NK-Cell Populations In addition, we analyzed the potential association between these gene mutations and both the lineage and biological features of clonal cells, the distribution of normal residual immune cells in blood, and other clinical features of the disease, including patient outcome. Here we investigated the frequency and type of somatic mutations of the STAT3 and STAT5B genes in (purified) T- and NK-LGLs from a large series of T-LGLL and CLPD-NK patients. Similarly, the potential impact of STAT3 mutations on disease behavior and patient outcome remains to be confirmed. Although STAT3/5B mutations present in LGLL are discussed in the WHO 2016 classification of hematological malignancies, its routine (clinical) utility as “clonal” markers of disease-particularly in cases showing expansion of cytotoxic T cells other than TCD8 +-LGLL (i.e., Tγδ +-LGLL)-still remains to be established. In contrast, STAT5B mutations have been reported to be associated with TCD4 +-LGLL (6/11 cases), while rarely (<2%) detected in both TCD8 +-LGLL and CLPD-NK. Thus, STAT3 mutations have been reported in between 21% and 73% of TCD8 +-LGLL and in 13–70% of CLPD-NK, depending on the sensitivity of the approach used. STAT3 and STAT5B (signal transducer and activator of transcription 3 and 5B genes) activating somatic mutations have been identified in a subset of LGLL. aggressive) disease behavior have been established for T-LGLL and CLPD-NK. So far, no reliable predictors of (indolent vs. In addition, clonal/oligoclonal LGLs are also frequently detected in blood of asymptomatic subjects, either transiently (i.e., after allogeneic hematopoietic stem cell transplantation or solid organ transplantation) or persistently (i.e., in the elderly). reactive/oligoclonal T cells, together with the lack of an universal marker of clonality for NK cells. This is mostly due to the absence in a significant fraction of patients of tumor-associated phenotypic and/or molecular markers of clonality that would allow clear cut distinction among expansions of clonal vs. Īt present, diagnosis of LGLL remains a challenge. In a few cases (<5%) transformation to aggressive leukemia has been reported. T-LGLL and CLPD-NK usually show an indolent clinical course, which is often associated with autoimmune conditions-e.g., cytopenias-and recurrent infections, that require therapeutic interventions. Most LGLL cases derive from TCRαβ +CD4 −CD8 + T lymphocytes (TCD8 +), less frequently from TCRαβ +CD4 +CD8 −/+lo T cells (TCD4 +), TCRγδ + T cells (Tγδ +) or NK cells, and rarely from other cytotoxic cells (i.e., TCRαβ +CD4 -CD8 −/+lo double-negative T cells -Tαβ +DN-). According to their normal counterpart, LGL leukemia (LGLL) is classified as T-cell LGLL (T-LGLL) or CLPD of natural killer (NK) cells (CLPD-NK). Leukemia of large granular lymphocytes (LGLs) is a rare chronic lymphoproliferative disorder (CLPD) defined by an unexplained and persistent (>6 months) expansion (usually >2 × 10 9/L) of clonal LGL cells in blood. 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. ![]() 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. STAT3-mutated T-LGLL/CLPD-NK showed overall reduced ( p < 0.05) blood counts of most normal leukocyte subsets, with a higher rate (vs. 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 ( 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. Seventeen non-LGL T-CLPD patients and 628 age-matched healthy donors were analyzed as controls. 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. 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.
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