Systematic STAT3 sequencing in patients with unexplained cytopenias identifies unsuspected large granular lymphocytic leukemia.
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ABSTRACT:
SUBMITTER: Morgan EA
PROVIDER: S-EPMC5728102 | biostudies-literature | 2017 Sep
REPOSITORIES: biostudies-literature
Publications
Systematic <i>STAT3</i> sequencing in patients with unexplained cytopenias identifies unsuspected large granular lymphocytic leukemia.
Morgan Elizabeth A EA Lee Mark N MN DeAngelo Daniel J DJ Steensma David P DP Stone Richard M RM Kuo Frank C FC Aster Jon C JC Gibson Christopher J CJ Lindsley R Coleman RC
Blood advances 20170913 21
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Project description:BackgroundT-cell large granular lymphocytic leukemia is a rare lymphoproliferative disorder characterized by the expansion of clonal CD3+CD8+ cytotoxic T lymphocytes (CTLs) and often associated with autoimmune disorders and immune-mediated cytopenias.MethodsWe used next-generation exome sequencing to identify somatic mutations in CTLs from an index patient with large granular lymphocytic leukemia. Targeted resequencing was performed in a well-characterized cohort of 76 patients with this disorder, characterized by clonal T-cell-receptor rearrangements and increased numbers of large granular lymphocytes.ResultsMutations in the signal transducer and activator of transcription 3 gene (STAT3) were found in 31 of 77 patients (40%) with large granular lymphocytic leukemia. Among these 31 patients, recurrent mutational hot spots included Y640F in 13 (17%), D661V in 7 (9%), D661Y in 7 (9%), and N647I in 3 (4%). All mutations were located in exon 21, encoding the Src homology 2 (SH2) domain, which mediates the dimerization and activation of STAT protein. The amino acid changes resulted in a more hydrophobic protein surface and were associated with phosphorylation of STAT3 and its localization in the nucleus. In vitro functional studies showed that the Y640F and D661V mutations increased the transcriptional activity of STAT3. In the affected patients, downstream target genes of the STAT3 pathway (IFNGR2, BCL2L1, and JAK2) were up-regulated. Patients with STAT3 mutations presented more often with neutropenia and rheumatoid arthritis than did patients without these mutations.ConclusionsThe SH2 dimerization and activation domain of STAT3 is frequently mutated in patients with large granular lymphocytic leukemia; these findings suggest that aberrant STAT3 signaling underlies the pathogenesis of this disease. (Funded by the Academy of Finland and others.).
| S-EPMC3693860 | biostudies-literature
Project description:T-cell large granular lymphocyte (T-LGL) leukemia is characterized by clonal expansion of cytotoxic T cells resulting in cytopenia. The proliferation of clonal LGLs is caused by prolonged antigenic stimulation, which leads to apoptotic dysregulation owing mainly to the constitutive activation of survival pathways, notably the JAK/STAT pathway. Understanding how leukemic T-LGL persists can aid in the development of future immunosuppressive therapies. In this review, we summarize the diagnosis and current standard of therapy for T-LGL leukemia, as well as recent advances in clinical trials.
| S-EPMC10133854 | biostudies-literature
Project description:Large granular lymphocytic leukemia (LGLL) is a lymphoproliferative disorder of older adults characterized by the clonal expansion of cytotoxic T/natural killer cells due to constitutive pro-survival signaling. In recent years, it has become clear that cytokines and their receptors are aberrantly expressed in LGLL cells. The exact initiation process of LGLL is unknown, although several cytokine-driven mechanisms have emerged. Elevated levels of several cytokines, including interleukin-15 (IL-15) and platelet-derived growth factor (PDGF), have been described in LGLL patients. Evidence from humans and animal models has shown that cytokines may also contribute to the co-occurrence of a wide range of autoimmune diseases seen in patients with LGLL. The goal of this review is to provide a comprehensive analysis of the link between cytokines and pro-survival signaling in LGLL and to discuss the various strategies and research approaches that are being utilized to study this link. This review will also highlight the importance of cytokine-targeted therapeutics in the treatment of LGLL.
| S-EPMC8960188 | biostudies-literature
Project description:BackgroundThe molecular pathogenesis of T-cell large granular lymphocytic leukemia (T-LGLL), a mature T-cell leukemia arising commonly from T-cell receptor αβ-positive CD8+ memory cytotoxic T cells, is only partly understood. The role of deregulated methylation in T-LGLL is not well known. We analyzed the epigenetic profile of T-LGLL cells of 11 patients compared to their normal counterparts by array-based DNA methylation profiling. For identification of molecular events driving the pathogenesis of T-LGLL, we compared the differentially methylated loci between the T-LGLL cases and normal T cells with chromatin segmentation data of benign T cells from the BLUEPRINT project. Moreover, we analyzed gene expression data of T-LGLL and benign T cells and validated the results by pyrosequencing in an extended cohort of 17 patients, including five patients with sequential samples.ResultsWe identified dysregulation of DNA methylation associated with altered gene expression in T-LGLL. Since T-LGLL is a rare disease, the samples size is low. But as confirmed for each sample, hypermethylation of T-LGLL cells at various CpG sites located at enhancer regions is a hallmark of this disease. The interaction of BLC11B and C14orf64 as suggested by in silico data analysis could provide a novel pathogenetic mechanism that needs further experimental investigation.ConclusionsDNA methylation is altered in T-LGLL cells compared to benign T cells. In particular, BCL11B is highly significant differentially methylated in T-LGLL cells. Although our results have to be validated in a larger patient cohort, BCL11B could be considered as a potential biomarker for this leukemia. In addition, altered gene expression and hypermethylation of enhancer regions could serve as potential mechanisms for treatment of this disease. Gene interactions of dysregulated genes, like BLC11B and C14orf64, may play an important role in pathogenic mechanisms and should be further analyzed.
| S-EPMC9664638 | biostudies-literature
Project description:Large granular lymphocytic (LGL) leukemia is a rare form of low grade leukemia characterized by large cytotoxic T cells or natural killer cells on morphological examination. Immunosuppressive therapy is employed as first-line therapy. Treatment options in refractory cases include the anti-CD52 antibody alemtuzumab and purine analogues. We report a rare case that responded to the anti-CD20 monoclonal antibody rituximab. A 77-year-old female presented with complaints of fatigue, fever, and chills of 3 months' duration. A CBC showed that pancytopenia with an absolute neutrophil count (ANC) was 0. Peripheral blood flow cytometry detected increased number of T cell large granular lymphocytes and T cell receptor rearrangement study detected a clonal T cell population. Bone marrow biopsy showed peripheral T cell lymphoma, most consistent with T-large granulocytic leukemia. The patient was treated with prednisone and oral cyclophosphamide for four months with no response. Thereafter, she received four weekly infusions of rituximab with improvement in her blood counts. A response to rituximab in refractory cases such as ours has been reported and may guide us towards exploring other immune-based therapeutics in this rare disease.
| S-EPMC5539931 | biostudies-other
Project description:Large granular lymphocytic (LGL) leukemia is characterized by clonal expansion of cytotoxic T cells or natural killer cells. Recently, somatic mutations in the signal transducer and activator of transcription 3 (STAT3) gene were discovered in 28% to 40% of LGL leukemia patients. By exome and transcriptome sequencing of 2 STAT3 mutation-negative LGL leukemia patients, we identified a recurrent, somatic missense mutation (Y665F) in the Src-like homology 2 domain of the STAT5b gene. Targeted amplicon sequencing of 211 LGL leukemia patients revealed 2 additional patients with STAT5b mutations (N642H), resulting in a total frequency of 2% (4 of 211) of STAT5b mutations across all patients. The Y665F and N642H mutant constructs increased the transcriptional activity of STAT5 and tyrosine (Y694) phosphorylation, which was also observed in patient samples. The clinical course of the disease in patients with the N642H mutation was aggressive and fatal, clearly different from typical LGL leukemia with a relatively favorable outcome. This is the first time somatic STAT5 mutations are discovered in human cancer and further emphasizes the role of STAT family genes in the pathogenesis of LGL leukemia.
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Project description:NK-large granular lymphocytic leukemia (NK-LGLL) is a rare chronic lymphoproliferative disorder and displays heterogeneity that remains insufficiently defined. CD56 plays a pivotal role in NK-cell maturation linked to cytotoxicity. However, whether CD56 might be associated with distinctive characteristics in NK-LGLL has not been determined. Hence, this study aims to explore potential associations between CD56 and clinical and biological features in 47 patients with NK-LGLL. Above all, anemia (57.4%) was the most prevalent symptom. Patients treated with immunosuppressive therapy showed a favorable outcome with 87.0% achieving remission. Furthermore, when stratifying patients by CD56 expression on tumor cells, the subset of 28 patients (59.6%) with diminished CD56 expression was frequently relevant to symptomatic disease (92.9% vs 15.8%, P < .001), comprising anemia (85.7% vs 15.8%, P < .001), neutropenia (67.9% vs 0.0%, P < .001), and splenomegaly (42.9% vs 10.5%, P = .024). Additionally, this subset demonstrated exclusive STAT3 mutation (61.9% vs 0.0%, P = .003), elevated CD161 levels (54.5% vs 0.0%, P < .001), and bone marrow fibrosis (92.3% vs 50.0%, P = 0.006). Furthermore, they showed shorter time to first treatment (TTFT) (4-year TTFT: 66.7% vs 100.0%, P = .083) and first-line progression-free survival (PFS) (median PFS: 26.3 months vs not reached, P = .112). Overall, our data indicate that NK-LGLL patients with diminished CD56 expression represent a more aggressive subset compared to those with normal CD56 levels, underscoring the significance of CD56 as a potential prognostic marker and advancing our understanding of the underlying pathogenesis of NK-LGLL.
| S-EPMC11892551 | biostudies-literature
Project description:Purpose of reviewThe past decade in LGL leukemia research has seen increased pairing of clinical data with molecular markers, shedding new insights on LGL leukemia pathogenesis and heterogeneity. This review summarizes the current standard of care of LGL leukemia, updates from clinical trials, and our congruent improved understanding of LGL pathogenesis.Recent findingsVarious clinical reports have identified associations between stem, bone marrow, and solid organ transplants and incidence of LGL leukemia. There is also a potential for underdiagnosis of LGL leukemia within the rheumatoid arthritis patient population, emphasizing our need for continued study. Preliminary results from the BNZ-1 clinical trial, which targets IL-15 along with IL-2 and IL-9 signaling pathways, show some evidence of clinical response. With advances in our understanding of LGL pathogenesis from both the bench and the clinic, exciting avenues for investigations lie ahead for LGL leukemia.
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