Stat3 mutations impact on overall survival in large granular lymphocyte leukemia: a single-center experience of 205 patients

Barilà, Gregorio; Teramo, Antonella; Calabretto, Giulia; Vicenzetto, Cristina; Gasparini, Vanessa Rebecca; Pavan, Laura; Leoncin, Matteo; Vedovato, Susanna; Frigo, Anna Chiara; Facco, Monica; Semenzato, Gianpietro; Zambello, Renato

doi:10.1038/s41375-019-0644-0

Cited by 55 publications

(99 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The similarity with T-LGLL involves STAT3 gene, that is reported mutated also in CLPD-NK [ (17,38); Figure 1]. To note, our data indicate that STAT3 mutations seem to have a lower incidence, from 5.9 to 8.3%, in this disease as compared to T-LGLL (15,39). Other studies report a frequency of STAT3 mutations from 11 up to 40%; the two studies with the largest number of CLPD-NK patients indicate 15/50 (30%) and 5/40 (13%) cases with STAT3 mutation (17,40).…”

Section: Stat3 and Stat5b Mutationssupporting

confidence: 60%

“…Differently from T-LGLL, CLPD-NK appears to be devoid of STAT5b genetic lesions (15,38,39), with the only exception of the aggressive case discussed by Rajala et al, who subsequently developed ANKL (28).…”

Section: Stat3 and Stat5b Mutationsmentioning

confidence: 93%

“…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.…”

Section: Stat3 Mutationsmentioning

confidence: 99%

“…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).…”

Section: Stat3 Mutationsmentioning

confidence: 99%

“…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).…”

Section: Stat5b Mutationsmentioning

confidence: 99%

See 4 more Smart Citations

Insights Into Genetic Landscape of Large Granular Lymphocyte Leukemia

et al. 2020

Self Cite

View full text Add to dashboard Cite

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.

show abstract