Single-Cell Transcriptome Analysis Identifies Key Components of Tumor Microenvironment for Extranodal Natural Killer/T-cell lymphoma
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PROVIDER: PRJNA841847 | ENA |
REPOSITORIES: ENA
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Project description:Extranodal natural killer/T-cell lymphoma (NKTCL) is an aggressive Epstein-Barr virus (EBV)-associated lymphoma with heterogeneous tumor behaviors and clinical outcomes. Here, we profiled tumor microenvironment (TME) of NKTCL through single-cell transcriptome analysis of 137,304 cells from 10 tumor-blood pairs. We identified six malignant subtypes with diverse transcriptional signatures, among which LMP1+ NK_C9_CXCL13 was characterized with oncogenic and immunosuppressive potentials as well as an axial role in malignant transformation. Moreover, ligand-receptor analyses and multiplex immunofluorescent staining assays revealed intensive interactions among malignant NK, tumoral myeloid, and T cells, fostering immunosuppressive TME in NKTCL. Furthermore, co-culture assays revealed that malignant cells induced the development of immunosuppressive and pro-tumorigenic tumor-associated macrophages (TAMs) through high expression of CSF1 and hampered the recruitment of normal NK cells through broad secretion of a dipeptidylpeptidase DPP4 in NKTCL. Lastly, we revealed the inter-patient heterogeneity of NKTCL with distinct EBV transcription and TAM infiltration in multiple patient cohorts, of which high and low were favorable prognostic indicators for NKTCL patients, respectively. Collectively, for the first time to our knowledge, our study dissects the heterogeneous composition of NKTCL TME at single-cell resolution, which provides insights into understanding the pathogenic mechanisms of NKTCL and developing novel therapeutic strategies against NKTCL.
2024-01-03 | GSE203663 | GEO
Project description:Oncogenic EZH2 is overexpressed and extensively involved in the pathophysiology of different cancers including extranodal natural killer/T-cell lymphoma (NKTL). However, the mechanisms regarding EZH2 upregulation is poorly understood, and it still remains untargetable in NKTL. In this study, we examine EZH2 protein turnover in NKTL and identify MELK kinase as a regulator of EZH2 ubiquitination and turnover. Using quantitative mass spectrometry (MS) analysis, we observed a MELK-mediated increase of EZH2 S220 phosphorylation along with a concomitant loss of EZH2 K222 ubiquitination, suggesting a phosphorylation-dependent regulation of EZH2 ubiquitination. MELK inhibition through both chemical and genetic means led to ubiquitination and destabilization of EZH2 protein. Importantly, we determine that MELK is upregulated in NKTL, and its expression correlates with EZH2 protein expression as determined by tissue microarray derived from NKTL patients. Interestingly, FOXM1, which connected MELK to EZH2 signaling in glioma, was not involved in mediating EZH2 ubiquitination. Furthermore, we identify USP36 as the deubiquitinating enzyme which deubiquitinates EZH2 at K222. These findings uncover an important role of MELK and USP36 in mediating EZH2 stability in NKTL. Moreover, MELK overexpression led to decreased sensitivity to Bortezomib treatment in NKTL based on deprivation of EZH2 ubiquitination. Therefore, modulation of EZH2 ubiquitination status by targeting MELK may be a new therapeutic strategy for NKTL patients with poor Bortezomib response.
2019-08-26 | PXD015008 | Pride
Project description:We performed a comprehensive genome-wide miRNA expression profiling (MEP) of extranodal nasal-type Natural Killer/T-cell lymphoma (NKTL) using formalin fixed paraffin-embedded tissue (FFPE) (n=30) and NK cell lines (n=6) in comparison with normal NK cells, with the objective of understanding the pathogenetic role of miRNA deregulation in NKTL. Total RNA, including miRNA, were extracted using Ambion Recoverall Kit and profiled using Agilent human miRNA V2.
2011-11-23 | E-GEOD-31377 | biostudies-arrayexpress
Project description:Extranodal natural killer/T cell lymphoma (ENKTL) is an aggressive, rare lymphoma of natural killer (NK) cell origin with very poor clinical outcomes and no effective targeted therapies. Improved understanding of the underlying biology of the disease is critical to design more effective treatment. Here we used phenotypic and molecular profiling including epigenetic analyses to investigate how ENKTL ontogeny relates to normal NK cell development. We demonstrate that neoplastic NK cells are stably but reversibly arrested at earlier stages of NK cell maturation. Genes downregulated in the tumors that demonstrated the most epigenetic immaturity were associated with polycomb silencing along with genomic gain and overexpression of EZH2. ENKTL cells exhibited a remarkable degree of genome-wide DNA hypermethylation. Tumor-specific DNA methylation gains were associated with polycomb-marked regions, involved the silencing of hundreds of genes (many involved in NK cell development), and loss of transcription factor binding. To investigate therapeutic targeting of the epigenetic developmental blockade, we treated novel PDX models of ENKTL with the DNA hypomethylating agent, 5-azacytidine. Treatment led to reduction of DNA methylation, re-expression of NK cell developmental genes, phenotypic NK cell differentiation, and prolongation of survival. These studies lay the foundation for epigenetic-directed therapy targeting the developmental blockade in ENKTL.
2022-01-12 | GSE169644 | GEO
Project description:Identification and targeting of the developmental blockade in extranodal natural killer/T cell lymphoma
| PRJNA717261 | ENA
Project description:We performed a comprehensive genome-wide miRNA expression profiling (MEP) of extranodal nasal-type Natural Killer/T-cell lymphoma (NKTL) using formalin fixed paraffin-embedded tissue (FFPE) (n=30) and NK cell lines (n=6) in comparison with normal NK cells, with the objective of understanding the pathogenetic role of miRNA deregulation in NKTL.
2011-11-23 | GSE31377 | GEO
Project description:Extranodal natural killer/T cell lymphoma (ENKTL) is an aggressive, rare lymphoma of natural killer (NK) cell origin with very poor clinical outcomes and no effective targeted therapies. Improved understanding of the underlying biology of the disease is critical to design more effective treatment. Here we used phenotypic and molecular profiling including epigenetic analyses to investigate how ENKTL ontogeny relates to normal NK cell development. We demonstrate that neoplastic NK cells are stably but reversibly arrested at earlier stages of NK cell maturation. Genes downregulated in the tumors that demonstrated the most epigenetic immaturity were associated with polycomb silencing along with genomic gain and overexpression of EZH2. ENKTL cells exhibited a remarkable degree of genome-wide DNA hypermethylation. Tumor-specific DNA methylation gains were associated with polycomb-marked regions, involved the silencing of hundreds of genes (many involved in NK cell development), and loss of transcription factor binding. To investigate therapeutic targeting of the epigenetic developmental blockade, we treated novel PDX models of ENKTL with the DNA hypomethylating agent, 5-azacytidine. Treatment led to reduction of DNA methylation, re-expression of NK cell developmental genes, phenotypic NK cell differentiation, and prolongation of survival. These studies lay the foundation for epigenetic-directed therapy targeting the developmental blockade in ENKTL.
2022-01-12 | GSE169643 | GEO
Project description:Identification and targeting of the developmental blockade in extranodal natural killer/T cell lymphoma [RNA-seq]
| PRJNA717266 | ENA
Project description:Identification and targeting of the developmental blockade in extranodal natural killer/T cell lymphoma [850K/EPIC DNA methylation]
| PRJNA717265 | ENA
Project description:Natural killer/T-cell (NK/T) lymphomas represent a group of rare tumors of NK and NK-T cells. The World Health Organization classifies NK-cell tumors into three types, extranodal NK/T-cell lymphomas (ENKL, nasal and non-nasal), NK-cell leukemias, and a blastic variant (CD4-positive, CD56-positive hematodermic neoplasms). We focus our review to the current concepts in biology and treatment of ENKL. Though considerable advances have been made in our understanding of NK-cell biology, malignant transformation including the role of Epstein-Barr virus, and prognosis, the rare nature of ENKL and its heterogeneity limit the ability to standardize therapy. Radiotherapy is fundamental to treatment of early-stage disease with a role for chemoradiotherapy among high-risk patients. The clinical course of advanced disease is highly aggressive with frequent chemotherapy resistance and a poor prognosis. Therapeutic approaches to advanced-stage or relapsed and refractory disease, including the appropriate sequence of chemotherapy, combined modality therapy, and stem cell transplantation is not well-established. International and multicenter clinical trials are needed for this rare and aggressive disease.
| S-EPMC5568825 | biostudies-other