Recurrent GNAQ mutation encoding T96S in natural killer/T cell lymphoma.
Ontology highlight
ABSTRACT:
SUBMITTER: Li Z
PROVIDER: S-EPMC6746819 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:To identify protein binding partners of wild-type or Gαq T96S mutants using immunoprecipitation coupled to mass spectrometry.
2019-09-25 | PXD013285 | Pride
Project description:Natural killer/T-cell lymphoma (NKTCL) is an incurable aggressive T-cell lymphoma closely correlated with Epstein‒Barr virus (EBV) infection. Chronic and consistent viral infection induces T-cell exhaustion. Herein, we describe T-cell dysfunction in NKTCL patients for the first time. Peripheral blood mononuclear cells (PBMCs) from age-matched healthy donors (HDs) and NKTCL patients were collected, and lymphocyte distributions, multiple surface inhibitory receptors (IRs), effector cytokine production and cell proliferation were determined by flow cytometry. PBMCs from HDs were cocultured with NKTCL cell lines to verify the clinical findings. IR expression was further assessed in NKTCL tumor biopsies using multiplex immunohistochemistry (mIHC). NKTCL patients have higher frequencies than HDs of inhibitory T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSCs). T-cell distribution also varies between NKTCL patients and HDs. T cells from NKTCL patients demonstrated higher expression levels of multiple IRs than HDs. Meanwhile, T-cell proliferation and interferon-γ production was significantly reduced in NKTCL patients. More importantly, the number of EBV-specific cytotoxic cells was lower in NTKCL patients, and these cells demonstrated upregulation of multiple IRs and secreted fewer effector cytokines. Interestingly, NKTCL cells caused normal PBMCs to acquire T-cell exhaustion phenotypes and induced generation of Tregs and MDSCs. In line with ex vivo finding, mIHC results showed that CD8+ T cells from NKTCL tumor biopsies expressed much higher level of IRs compared with reactive lymphoid hyperplasia individuals. The immune microenvironment of NKTCL patients exhibited T-cell dysfunction and accumulation of inhibitory cell components, which may contribute to impaired antitumor immunity.
| S-EPMC10210841 | biostudies-literature
Project description:Nasal natural killer (NK)/T-cell lymphoma (NL) frequently co-expresses Fas (Apo-1/CD95) and Fas ligand (FasL), but the tumor cells seldom undergo apoptosis. To determine the reason for failure of apoptosis, we examined Fas mRNA expression in 23 NL cases by reverse transcriptase-polymerase chain reaction and sequenced the entire coding region of the Fas gene in 15 of these cases for which the full-length Fas cDNA could be amplified. The reverse transcriptase-polymerase chain reaction analysis revealed that all of the 23 cases expressed Fas mRNA and the sequencing results showed that in addition to the commonly expressed wild-type Fas mRNA and four alternative splice variants detected in 7 cases, mutant Fas transcripts were present in 9 of the 15 (60%) cases sequenced. With confirmation of some Fas mutations at the gene level, 12 deletions in nine cases and one insertion in one case were eventually identified. To rule out any potential polymerase chain reaction artifacts, the same protocol was used to examine 10 reactive tonsils as a control. No aberrant transcripts associated with deletions were detected in these tonsils except for three alternative splice variants. All of the deletion variants detected in NL contained N-terminal preligand assembly domain but not C-terminal death domain and/or transmembrane domain. Co-detection of the wild-type allele and the mutated Fas alleles without the death domain suggested that a dominant-negative mechanism could block the apoptosis signaling. Moreover, loss of the transmembrane domain could protect the tumor cells from apo-ptosis by producing a soluble form of the Fas receptor. The actuarial 3-year survivals leveled off at 15% for patients carrying the Fas mutations and/or splice variants in the lesions and 49% for those carrying the wild type only, but the difference did not reach statistical significance on the univariate analysis (P = 0.396). Taken together, the findings in this study suggest that frequent Fas gene mutations in NL can result in resistance to apoptosis and may contribute to the pathogenesis of NL by adding to the tumor immune privilege.
| S-EPMC1850920 | biostudies-literature
Project description:Extranodal natural killer/T-cell lymphoma, nasal type (ENKL), is a rare malignancy of Non-Hodgkin lymphoma characterized by an aggressive clinical course and poor prognosis. It shows strong association with Epstein-Barr virus infection and occurs more commonly in Asia and Latin America. Various genetic alterations have been identified in ENKL by gene expression profiling and sequencing techniques. The frequent deletion of chromosome 6q21 was reported to lead to the silence of several tumor suppressor genes. Also, there have been novel genetic mutations that were recently uncovered and were found to frequently activate several oncogenic pathways, including the JAK/STAT, NF-?B, and MAPK pathways. Besides, we believe that deregulated single genes and epigenetic dysregulation might be relevant to the mechanism of this disease and thus, may have the potential to shed lights on the development of new therapeutic strategies. The consensus on the standard treatment for ENKL has not yet been currently established. For localized ENKL patients, radiotherapy with concurrent chemotherapy and sequential patterns of chemotherapy and radiotherapy are recommended as first-line therapy. As for advanced or relapsed/refractory ENKL patients, the application of non-anthracycline-containing regimens have significantly improved the clinical outcome, contributing to higher response rate, longer overall survival and progression-free survival. Hematopoietic stem cell transplantation is widely recommended for consolidation after a complete remission or partial remission has been achieved. The anti-programmed death 1 antibody, an immune checkpoint inhibitor, has demonstrated favorable results in treating relapsed or refractory ENKL. Of the current ENKL treatment, researchers are still striving to validate how radiotherapy and chemotherapy should be optimally combined and which of the non-anthracycline-containing regimens is superior. In this review, we summarize the main genetic alterations frequently found in ENKL and their role in providing new insights into the therapeutic targets of this disease, and highlight the recent findings regarding new biologic markers, novel therapeutic strategies applied to this intriguing neoplasm.
| S-EPMC6527808 | biostudies-literature
Project description:Natural killer/T-cell lymphoma (NKTCL) is a highly invasive subtype of non-Hodgkin lymphoma, typically positive for cytoplasmic CD3, CD56, cytotoxic markers, including granzyme B and TIA1, and Epstein-Barr virus (EBV). The current treatment methods for NKTCL are associated with several drawbacks. For example, chemotherapy can lead to drug resistance, while treatment with radiotherapy alone is inadequate and results in frequent relapses. Moreover, hematopoietic stem cell transplantation exhibits limited efficacy and is not well recognized by domestic and foreign experts. In recent years, immunotherapy has shown good clinical results and has become a hot spot in cancer research. Clinical activity of targeted antibodies, such as daratumumab (anti-CD38 antibody) and brentuximab vedotin (anti-CD30 antibody), have been reported in NKTCL. Additionally, dacetuzumab and Campath-1H have demonstrated promising results. Further encouraging data have been obtained using checkpoint inhibitors. The success of these immunotherapy agents is attributed to high expression levels of programmed death-ligand 1 in NKTCL. Furthermore, anti-CCR4 monoclonal antibodies (mAbs) exert cytotoxic actions on both CCR4+ tumor cells and regulatory T cells. Depletion of these cells and the long half-life of anti-CCR4 mAbs result in enhanced induction of antitumor effector T cells. The role of IL10 in NKTCL has also been investigated. It has been proposed that exploitation of this cytokine might provide potential novel therapeutic strategies. Cellular immunotherapy with engineered cytotoxic T lymphocytes targeted against LMP1 and LMP2 has shown promising results and sustained remission. Cellular immunotherapy may be used either as maintenance therapy following initial induction chemotherapy or in cases of relapsed/refractory disease. The present review outlines the known immunotherapy targets for the treatment of NKTCL.
| S-EPMC7877170 | biostudies-literature
Project description:Case summaryA 7-year-old mixed-breed cat presented with subcutaneous oedema and erythema extending from the right axilla to the abdomen. Fine-needle aspiration of the subcutaneous lesion revealed large, atypical, round cells. A clonality analysis for the T-cell receptor-gamma and immunoglobulin heavy chain genes showed no clonal rearrangement. The presumed diagnosis was lymphoma and the cat was treated with prednisolone and L-asparaginase but died 78 days after initial treatment. At necropsy, an oedematous subcutaneous mass in the right axilla, hepatomegaly, splenomegaly and lymphadenopathy of the mediastinum and left axilla were observed. Histopathological examination revealed diffuse infiltration of large atypical round cells in the subcutaneous mass, liver, spleen, lymph nodes and bone marrow. Immunohistochemically, the tumour cells were strongly positive for CD56, and negative for CD3, CD20, CD79a, CD57, granzyme B and perforin. Based on these findings, the cat was diagnosed with blastic natural killer (NK) cell lymphoma/leukaemia.Relevance and novel informationHere, we report the pathological and clinical findings of NK cell lymphoma/leukaemia in a cat. The antibody for human CD56, a diagnostic marker for human NK cell neoplasms, showed cross-reactivity with feline CD56 by immunohistochemistry and Western blotting analysis. The antibody could be a useful diagnostic marker for feline NK cell neoplasms.
| S-EPMC6628536 | biostudies-literature
Project description:Natural-killer/T cell lymphoma (NKTCL) represents the most common subtype of extranodal lymphoma with aggressive clinical behavior. Prevalent in Asians and South Americans, the pathogenesis of NKTCL remains to be fully elucidated. Using system biology techniques including genomics, transcriptomics, epigenomics, and metabolomics, novel biomarkers and therapeutic targets have been revealed in NKTCL. Whole-exome sequencing studies identify recurrent somatic gene mutations, involving RNA helicases, tumor suppressors, JAK-STAT pathway molecules, and epigenetic modifiers. Another genome-wide association study reports that single nucleotide polymorphisms mapping to the class II MHC region on chromosome 6 contribute to lymphomagenesis. Alterations of oncogenic signaling pathways janus kinase-signal transducer and activator of transcription (JAK-STAT), nuclear factor-?B (NF-?B), mitogen-activated protein kinase (MAPK), WNT, and NOTCH, as well as epigenetic dysregulation of microRNA and long non-coding RNAs, are also frequently observed in NKTCL. As for metabolomic profiling, abnormal amino acids metabolism plays an important role on disease progression of NKTCL. Of note, through targeting multiple omics aberrations, clinical outcome of NKTCL patients has been significantly improved by asparaginase-based regimens, immune checkpoints inhibitors, and histone deacetylation inhibitors. Future investigations will be emphasized on molecular classification of NKTCL using integrated analysis of system biology, so as to optimize targeted therapeutic strategies of NKTCL in the era of precision medicine.
| S-EPMC6280527 | biostudies-literature
Project description:Natural killer T cell lymphoma (NKTL) is an aggressive disease with very poor treatment outcomes in the advanced stages. With chemotherapy, initial response rates to treatment are high but responses are short lived. A better understanding of the complex molecular pathogenesis of this disease is essential in order to design and develop better therapeutics with improved efficacy. This review aims to summarise the key pathogenic mechanisms in NKTL which may have significant prognostic and therapeutic implications.
| S-EPMC6420729 | biostudies-literature
Project description:Natural killer (NK) cell lymphomas are a group of rare but highly aggressive malignancies. Clinically, they can be divided into nasal NK cell lymphomas, nonnasal NK cell lymphomas, and aggressive NK cell lymphoma/leukemia. To determine the patterns of genetic deletions in these tumors, we performed loss of heterozygosity (LOH) analysis on 15 cases (11 nasal and four nonnasal), and fluorescence in situ hybridization on three cases of aggressive lymphoma/leukemia. A panel of 41 microsatellite loci on chromosomes 6q, 11q, 13q, and 17p were investigated. LOH at chromosomes 6q and 13q was frequently detected in NK cell lymphomas, being found in 80 and 66.7% of cases, respectively. LOH at chromosomes 11q and 17p was less common, being found in 28.6 and 30.8% of cases, respectively. Most tumors showed multiple loci deletions at different chromosomal regions, but several patterns of LOH could be defined. LOH at chromosome 6q was found in 90.9% of nasal NK cell lymphomas, but only in 50% of nonnasal NK cell lymphomas. LOH at chromosome 13q was found in 63.6% of nasal NK cell lymphomas and 75% of nonnasal NK cell lymphomas. For nasal NK cell lymphomas, LOH at 13q was found in 33.3% of cases at presentation, but 100% of cases at relapse. Five tumors showed LOH in only one chromosomal region, involving 6q in three cases (two nasal and one nonnasal), and 13q in two cases (both nonnasal). For the three cases of aggressive NK cell lymphoma/leukemia studied by fluorescence in situ hybridization, DNA loss at 13q14 and 17p13 regions were demonstrated. 17p13 seemed to be more commonly involved in aggressive than nasal and nonnasal NK cell lymphomas. Our results suggested that consistent patterns of LOH could be defined in NK cell malignancies. These deleted loci may contain genes important in the initiation and progression of this lymphoma.
| S-EPMC1885756 | biostudies-literature
Project description:The rapidly increasing use of high-throughput screening had produced a plethora of expanding knowledge on the molecular basis of natural killer/T-cell lymphoma (NKTCL), which in turn has revolutionized the treatment. Specifically, the use of asparaginase-containing regimens has led to substantial improvement in survival outcomes in NKTCL patients. Novel treatment strategies that are currently under development include cell-surface-targeted antibodies, immune checkpoint inhibitors, Epstein-Barr virus targeted cytotoxic T lymphocyte, immunomodulatory agents, chimeric antigen receptor T cells, signaling pathway inhibitors and epigenetic targeted agents. In almost all cases, initial clinical studies of newly developed treatment are conducted in patients relapsed, and refractory NKTCL due to very limited treatment options. This review summarizes the results of these novel treatments for NKTCL and discusses their potential for likely use in NKTCL in a wider setting in the future.
| S-EPMC10362755 | biostudies-literature