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.
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.
Project description:NK-cell lymphoma shares strikingly similar molecular features with a distinct subset of gamma-delta T-cell lymphoma. Gene expression profiling of NK-cell lymphoma patient samples was performed to investigate whether molecular signatures can be used to identify entities of peripheral T-cell lymphoma (PTCL) with NK-cell-like features. Gene expression profiling was performed on NK-cell maligancies to examine extranodal NK/T-cell lymphoma (ENKTL) and aggressive NK-cell leukemia (ANKL) and well-characterized cell lines of NK- and T-cell lineages to define molecular classifiers that can distinguish ENKTL from other lymphomas.
Project description:The molecular biology of the primary nodal EBV-positive variant of PTCL (PTCL-EBV) and its relationship with extranodal NK/T-cell lymphoma (ENKTL) and peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) remains poorly understood. In this study, we assessed the relationship between the three diseases using gene and EBV miRNA expression profiling, and copy number aberration (CNA) analyses and attempted to characterize the degree of genomic instability (GI). This series is the oncoscan CNA data of 77 NKTL samples.
2021-11-27 | GSE160118 | GEO
Project description:Effect of SRPK1 inhibitor in ENKTL cells
