Insights Into Genetic Landscape of Large Granular Lymphocyte Leukemia

Abstract

Large granular lymphocyte leukemia (LGLL) is a chronic proliferation of clonal cytotoxic lymphocytes, usually presenting with cytopenias and yet lacking a specific therapy. The disease is heterogeneous, including different subsets of patients distinguished by LGL immunophenotype (CD8+ Tαβ, CD4+ Tαβ, Tγδ, NK) and the clinical course of the disease (indolent/symptomatic/aggressive). Even if the etiology of LGLL remains elusive, evidence is accumulating on the genetic landscape driving and/or sustaining chronic LGL proliferations. The most common gain-of-function mutations identified in LGLL patients are on STAT3 and STAT5b genes, which have been recently recognized as clonal markers and were included in the 2017 WHO classification of the disease. A significant correlation between STAT3 mutations and symptomatic disease has been highlighted. At variance, STAT5b mutations could have a different clinical impact based on the immunophenotype of the mutated clone. In fact, they are regarded as the signature of an aggressive clinical course with a poor prognosis in CD8+ T-LGLL and aggressive NK cell leukemia, while they are devoid of negative prognostic significance in CD4+ T-LGLL and Tγδ LGLL. Knowing the specific distribution of STAT mutations helps identify the discrete mechanisms sustaining LGL proliferations in the corresponding disease subsets. Some patients equipped with wild type STAT genes are characterized by less frequent mutations in different genes, suggesting that other pathogenetic mechanisms are likely to be involved. In this review, we discuss how the LGLL mutational pattern allows a more precise and detailed tumor stratification, suggesting new parameters for better management of the disease and hopefully paving the way for a targeted clinical approach.

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

“…At the same time, it further confirms that STAT3 mutations in LGL do not occur at early stages of hematopoiesis. These results, together with the coexistence of ≥2 distinct LGL clones in up to one third of TCD8 + -LGLL cases, support previous studies suggesting that chronic (viral or autologous) antigen stimulation might be involved in the pathogenesis of oligoclonal/clonal LGL expansions and the sequential selection and expansion of a progressively smaller number of LGL clones [10,[50][51][52][53]. If this hypothesis holds true, survival of the antigen-selected LGL population(s) might then be maintained via upregulation of specific activation pathways, particularly those involving JAK/STAT signaling [53].…”

“…These results, together with the coexistence of ≥2 distinct LGL clones in up to one third of TCD8 + -LGLL cases, support previous studies suggesting that chronic (viral or autologous) antigen stimulation might be involved in the pathogenesis of oligoclonal/clonal LGL expansions and the sequential selection and expansion of a progressively smaller number of LGL clones [10,[50][51][52][53]. If this hypothesis holds true, survival of the antigen-selected LGL population(s) might then be maintained via upregulation of specific activation pathways, particularly those involving JAK/STAT signaling [53]. In line with this hypothesis, mutations in several genes other than STAT3 and STAT5B involved in this JAK/STAT signaling pathway, such as the IGSF3, JAK3, PTPRT, TTN, and USH2A genes, have also been sporadically reported in LGLL [25,27,28,54].…”

Hypoplastic Myelodysplastic Syndromes: Just an Overlap Syndrome?

“…LGL expansion may occur as a distinct mono-oligoclonal disease [ 48 ] or be associated with other conditions, including myeloid malignancies and autoimmune diseases. Clonality may be difficult to demonstrate, but some genetic lesions have been identified, including STAT3, STAT5b, and cytokine polymorphisms [ 49 ]. Interestingly, Jerez and Colleagues recently reported the presence of STAT3 mutations in 7% and 2.5% of MDS and AA, respectively, out of a large cohort of 507 patients [ 50 ].…”

High frequency of STAT3 gene mutations in T‐cell receptor (TCR)γδ‐type T‐cell large granular lymphocytic leukaemia: implications for molecular diagnostics

“…In CD4 + TCRαβ‐type LGLL, STAT5B is frequently mutated 6 . Mutations of the above‐mentioned genes were located mainly in the src‐homology (SH)‐2 domain, and are considered to be activating mutations 7 . On the other hand, the molecular basis of TCRγδ‐type LGLL is still uncertain.…”