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Identification and targeting of the developmental blockade in extranodal natural killer/T cell lymphoma [RNA-seq]

ABSTRACT: Identification and targeting of the developmental blockade in extranodal natural killer/T cell lymphoma [RNA-seq]

PROVIDER: PRJNA717266 | ENA |

REPOSITORIES: ENA

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Identification and targeting of the developmental blockade in extranodal natural killer/T cell lymphoma [RNA-seq]

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

Identification and targeting of the developmental blockade in extranodal natural killer/T cell lymphoma

Project description:Identification and targeting of the developmental blockade in extranodal natural killer/T cell lymphoma

| PRJNA717261 | ENA

Identification and targeting of the developmental blockade in extranodal natural killer/T cell lymphoma [850K/EPIC DNA methylation]

2022-01-12 | GSE169643 | GEO

Identification and targeting of the developmental blockade in extranodal natural killer/T cell lymphoma [850K/EPIC DNA methylation]

Project description:Identification and targeting of the developmental blockade in extranodal natural killer/T cell lymphoma [850K/EPIC DNA methylation]

| PRJNA717265 | ENA

miRNA expression profiling of NKTCL (Natural Killer/T-Cell Lymphoma) samples

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

miRNA expression profiling of NKTCL (Natural Killer/T-Cell Lymphoma) samples

2011-11-23 | GSE31377 | GEO

Expression profiling of Natural killer B cells

Project description:Investigation of global gene expression levels between B cells, Natural killer cells and Natural killer B cells Gene expression profiling using sorted B cells, Natural killer cells and Natural killer B cells from WT mouse spleen. Total RNA extracted from WT cells were quantified by the NanoDrop ND-1000 and RNA integrity was assessed by standard denaturing agarose gel electrophoresis. The sample preparation and microarray hybridization were performed based on the NimbleGenâs standard protocols.

2016-05-17 | E-GEOD-80063 | biostudies-arrayexpress

MELK mediates the stability of EZH2 throught site-specific phosphorylation in extranodal natural killer/T-cell lymphoma

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

Expression profiling of Natural killer B cells

Project description:Investigation of global gene expression levels between B cells, Natural killer cells and Natural killer B cells

2016-05-17 | GSE80063 | GEO

Transcription profiling of neonatal and adult mouse natural killer cells

Project description:Comparing global gene expression of neonatal and adult natural killer cells to determine if differences in gene expression suggest that different developmental pathways during hematopoiesis are followed in the fetal and adult mouse to produce mature natural killer cells.

2005-10-01 | E-MEXP-354 | biostudies-arrayexpress

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