Genomic landscape characterization of large granular lymphocyte leukemia with a systems genetics approach.
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ABSTRACT:
SUBMITTER: Coppe A
PROVIDER: S-EPMC5419584 | biostudies-literature | 2017 May
REPOSITORIES: biostudies-literature
Publications
Genomic landscape characterization of large granular lymphocyte leukemia with a systems genetics approach.
Coppe A A Andersson E I EI Binatti A A Gasparini V R VR Bortoluzzi S S Clemente M M Herling M M Maciejewski J J Mustjoki S S Bortoluzzi S S
Leukemia 20170207 5
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Project description:Large granular lymphocyte (LGL) leukemia comprises a group of rare lymphoproliferative disorders whose molecular landscape is incompletely defined. We leveraged paired whole-exome and transcriptome sequencing in the largest LGL leukemia cohort to date, which included 105 patients (93 T-cell receptor αβ [TCRαβ] T-LGL and 12 TCRγδ T-LGL). Seventy-six mutations were observed in 3 or more patients in the cohort, and out of those, STAT3, KMT2D, PIK3R1, TTN, EYS, and SULF1 mutations were shared between both subtypes. We identified ARHGAP25, ABCC9, PCDHA11, SULF1, SLC6A15, DDX59, DNMT3A, FAS, KDM6A, KMT2D, PIK3R1, STAT3, STAT5B, TET2, and TNFAIP3 as recurrently mutated putative drivers using an unbiased driver analysis approach leveraging our whole-exome cohort. Hotspot mutations in STAT3, PIK3R1, and FAS were detected, whereas truncating mutations in epigenetic modifying enzymes such as KMT2D and TET2 were observed. Moreover, STAT3 mutations co-occurred with mutations in chromatin and epigenetic modifying genes, especially KMT2D and SETD1B (P < .01 and P < .05, respectively). STAT3 was mutated in 50.5% of the patients. Most common Y640F STAT3 mutation was associated with lower absolute neutrophil count values, and N647I mutation was associated with lower hemoglobin values. Somatic activating mutations (Q160P, D170Y, L287F) in the STAT3 coiled-coil domain were characterized. STAT3-mutant patients exhibited increased mutational burden and enrichment of a mutational signature associated with increased spontaneous deamination of 5-methylcytosine. Finally, gene expression analysis revealed enrichment of interferon-γ signaling and decreased phosphatidylinositol 3-kinase-Akt signaling for STAT3-mutant patients. These findings highlight the clinical and molecular heterogeneity of this rare disorder.
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Project description: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+ T??, CD4+ T??, T??, 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 T?? 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.
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Project description:The bone marrow microenvironment in Large Granular Lymphocyte Leukemia (LGLL) patients has been unexplored for it’s role in the development of cytopenias, which lead to complications resulting in the most prominent causes of morbidity and mortality. We used microarrays on primary mesenchymal stem cell (MSC) cultures isolated from bone marrow aspirates from LGLL patients to identify genetic programs that may lead to the observed profibrotic and extrinsically senescent phenotype.
2013-04-20 | GSE37470 | GEO
Project description:The bone marrow microenvironment in Large Granular Lymphocyte Leukemia (LGLL) patients has been unexplored for it’s role in the development of cytopenias, which lead to complications resulting in the most prominent causes of morbidity and mortality. We used microarrays on primary mesenchymal stem cell (MSC) cultures isolated from bone marrow aspirates from LGLL patients to identify genetic programs that may lead to the observed profibrotic and extrinsically senescent phenotype. Isolated primary MSC cultures were maintained under reduced oxygen conditions (2%). All cultures displayed trilineage pluripotency (adipogenesis, osteogenesis, and chondrogenesis). For comparison, normal MSC cultures in early passage (p2-3; same number of population doublings as the LGLL MSCs) and later passage (p7-9; same time spent in culture as the LGLL MSCs) are included.
2013-04-20 | E-GEOD-37470 | biostudies-arrayexpress
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Project description:To characterize T-cell large granular leukemia in Asia, 22 Chinese patients from a single institute were reported, together with an analysis of 88 Asian and 272 Western patients identified from the literature. In our cohort, anemia due to pure red cell aplasia (PRCA) occurred in 15/22 (68%) of cases, being the most common indication for treatment. Neutropenia was only found in 8/22 (36%) cases, and recurrent infections, the most important clinical problem in Western patients, were not observed. None of our cases presented with rheumatoid arthritis. These clinical features were consistently observed when compared with the 88 other Asian patients. Combined data from our cohort and other Asian cases showed that Asian patients, compared with Western patients, had more frequent anemia (66/110, 60% versus 113/240, 47%; p=0.044), attributable to a much higher incidence of PRCA (52/110, 47% versus 6/143, 4%; p<0.001). However, Western patients presented more frequently than Asian patients with neutropenia (146/235, 62% versus 33/110, 30%; p<0.001) and splenomegaly (99/246, 40% versus 16/110, 15%; p< 0.001). Notably, Western patients were about eight to ten times more likely than Asian patients to have rheumatoid arthritis (73/272, 27% versus 4/106, 4%; p<0.001) and recurrent infections (81/272, 30% versus 3/107, 3%; p<0.001). These clinicopathologic differences have important implications on disease pathogenesis and treatment.
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Project description:Our results suggest that STAT3 can be activated independent of key oncogenic driver mutations in its SH2 domain in a subset of patients with large granular lymphocyte disorders. We examined the gene expression pattern in T-LGL leukemias compared to controls, and the impact of the presence of STAT3 mutations on the transcriptional regulation of a specific set of genes previously described.
2012-08-03 | GSE39838 | GEO
Project description:T cell large granular lymphocyte (T-LGL) leukemia features a clonal expansion of antigen-primed, competent, cytotoxic T lymphocytes (CTL). To systematically understand signaling components that determine the survival of CTL in T-LGL leukemia, we constructed a T-LGL survival signaling network by integrating the signaling pathways involved in normal CTL activation and the known deregulations of survival signaling in leukemic T-LGL. This network was subsequently translated into a predictive, discrete, dynamic model. Our model suggests that the persistence of IL-15 and PDGF is sufficient to reproduce all known deregulations in leukemic T-LGL. This finding leads to the following predictions: (i) Inhibiting PDGF signaling induces apoptosis in leukemic T-LGL. (ii) Sphingosine kinase 1 and NFkappaB are essential for the long-term survival of CTL in T-LGL leukemia. (iii) NFkappaB functions downstream of PI3K and prevents apoptosis through maintaining the expression of myeloid cell leukemia sequence 1. (iv) T box expressed in T cells (T-bet) should be constitutively activated concurrently with NFkappaB activation to reproduce the leukemic T-LGL phenotype. We validated these predictions experimentally. Our study provides a model describing the signaling network involved in maintaining the long-term survival of competent CTL in humans. The model will be useful in identifying potential therapeutic targets for T-LGL leukemia and generating long-term competent CTL necessary for tumor and cancer vaccine development.
| S-EPMC2571012 | biostudies-literature
Project description:Large granular lymphocyte (LGL) leukemia is a clonal lymphoproliferative disorder of cytotoxic lymphocytes characterized by an expansion of CD3(+) cytotoxic T lymphocytes or CD3(-) natural killer cells. Patients present with various cytopenias including neutropenia, anemia and thrombocytopenia. In addition, there is an association of T-cell large granular lymphocytic leukemia with rheumatoid arthritis. It is believed that LGL leukemia begins as an antigen-driven immune response with subsequent constitutive activation of cytotoxic T lymphocytes or natural killer cells through PDGF and IL-15 contributing to their survival. Consequently, this leads to a dysregulation of apoptosis and dysfunction of the activation-induced cell death pathway. Treatment of LGL leukemia is based on a low-dose immunosuppressive regimen using methotrexate or cyclophosphamide. However, no standard of therapy has been established, as large prospective trials have not been conducted. In addition, some patients are refractory to treatment. The lack of a curative therapy for LGL leukemia means that new treatment options are needed. Insight into the various dysregulated signaling pathways in LGL leukemia may provide novel therapeutic treatment modalities.
| S-EPMC3464048 | biostudies-literature
Project description:Our results suggest that STAT3 can be activated independent of key oncogenic driver mutations in its SH2 domain in a subset of patients with large granular lymphocyte disorders. We examined the gene expression pattern in T-LGL leukemias compared to controls, and the impact of the presence of STAT3 mutations on the transcriptional regulation of a specific set of genes previously described. Mononuclear cells were separated from peripheral blood by density gradient sedimentation (Mediatech, Herndon, VA, USA). LGL cells were separated by flow cytometric sorting using anti-VB and CD8 mAb as described previously. Healthy, donor-derived CD8+CD57+ cells were isolated by flow cytometric sorting using CD3, CD8, and CD57 mAb. Total RNA was extracted from cells using Trizol (Invitrogen, Carlsbad, CA, USA) Phase-Lock gel tubes (Eppendorf, Hamburg, Germany), cleaned RNAeasy columns (Qiagen, Valencia CA, USA), and dissolved diethylpyrocarbonate water. Total cRNA was prepared using the in vitro-transcribed (Affymetrix, Santa Clara, CA, USA) and hybridized to U133 arrays, according to the manufacturer's instructions (Affymetrix). All microarrays were examined for surface defects, grid placement, background intensity, housekeeping gene expression, and a 3:5 ratio of probe from genes of varying length. Expression analysis was conducted using standard Affymetrix analysis software algorithms (Microarray Suite 5.0). Comparative analysis between expression profiles was carried out on GeneSpring' software, Version 7.1 (Agilent, Clara, CA, USA). Scanned images of Affymetrix chips were converted spreadsheet numbers using Affymetrix proprietary GeneChip Operating software (GCOS).
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