Epigenetic Regulation of Differentially Expressed Genes in Cutaneous T Cell Lymphoma

皮肤T细胞淋巴瘤差异表达基因的表观遗传调控

• 批准号: 10490348
• 负责人: HENRY Keung WONG
• 金额: --
• 依托单位: CENTRAL ARKANSAS VETERANS HLTHCARE SYS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10490348
• 关键词: Address; Affect; Benign; Binding Sites; Biological; Biological Assay; Biological Markers; Chemicals; Chronic; Clinical; Complex; Consequentialism; Cross-Sectional Studies; Cutaneous T-cell lymphoma; DNA; DNA Methylation; DNA analysis; Data; Databases; Development; Diagnosis; Diagnostic Specificity; Diagnostic tests; Disease; Disease Progression; Early Diagnosis; Eczema; Enhancers; Enzymes; Epigenetic Process; Etiology; Evolution; Experimental Models; Exposure to; Gene Abnormality; Gene Expression; Gene Expression Profiling; General Population; Genes; Genetic; Genetic Heterogeneity; Genomic Instability; Genomics; Goals; Grant; Health; Hydrocarbons; Hypermethylation; Incidence; Indolent; Inflammation; Inflammatory; Informatics; Lead; Lesion; Life; Malignant - descriptor; Malignant Neoplasms; Maps; Methylation; Military Personnel; Monitor; Mutation; Mycosis Fungoides; Nature; Neoplastic Cell Transformation; Occupational; Oncogenic; Pain; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pesticides; Play; Process; Prognosis; Prognostic Marker; Pruritus; Psoriasis; Publishing; Quality of life; Regulator Genes; Regulatory Element; Reproducibility; Research; Resolution; Rest; Risk; Risk Factors; Role; Sensitivity Training Groups; Services; Severity of illness; Sezary Syndrome; Signal Transduction; Site; Skin; Sleep disturbances; Study models; T-Cell Lymphoma; T-Lymphocyte; TWIST1 gene; Technology; Training; Tumor Suppressor Genes; Variant; Veterans; advanced disease; base; cancer cell; cancer genome; cell growth; combat; demethylation; diagnostic biomarker; diagnostic value; differential expression; effective therapy; emotional distress; epigenetic regulation; experimental study; genome-wide; improved; insight; leukemia; loss of function; mRNA Expression; methylation biomarker; methylome; military veteran; neoplastic; new therapeutic target; novel; overexpression; permissiveness; personalized medicine; prevent; promoter; skin lesion; transcription factor; transcriptome; transcriptome sequencing; treatment strategy; tumor; tumorigenesis

Genomic instability and dysregulated epigenetic control are now both recognized as hallmarks of cancer, although the mechanisms responsible are poorly understood. Both lead to abnormal gene expression, and gains and losses of function that can promote oncogenesis. Tumor suppressor genes are often repressed by hypermethylation of CpG sites. Cancer genomes are also frequently globally hypomethylated. Hypomethylation of gene-regulatory elements, such as transcription factor binding sites and enhancers, may cause lineage-inappropriate “ectopic” gene expression, and activation of oncogenic pathways. Highly expressed genes specific to cancer cells make attractive positive biomarkers that may be useful in diagnostic tests, or new targets for therapy. Negative biomarkers resulting from loss of gene expression in cancer are problematic due to their indirect nature and nonspecificity. In contrast to the role of hypermethylation in cancer, the impact of hypomethylation is very understudied. Sezary syndrome (SS), an aggressive, leukemic variant of cutaneous T cell lymphoma (CTCL) is a good model for studies of cancer-associated hypomethylation because it is one of the most heavily hypomethylated cancers. SS, which has 6-8 fold higher incidence in the Veteran population, is marked by frequent mutations in epigenetic modulators, including enzymes involved in methyation and demethylation of DNA. We recently published a gene expression profiling study of malignant T cells in SS using high resolution microarrays, and identified a number of highly overexpressed genes specific to SS T cells (SS-HEG), that could function as positive biomarkers. We have also published our discovery that promoter hypomethylation is associated with overexpression of PLS3, GATA6, and TWIST1 genes in SS T cells, and that DNA methylation can regulate PLS3 gene expression. To more fully explore the effect of DNA methylation changes that may drive ectopic gene expression in SS, we have recently obtained genome wide DNA methylation profiles for SS T cells. Our preliminary data shows that additional SS-HEG are significantly hypomethylated in SS T cells, suggesting that DNA hypomethylation may contribute to overexpression of these genes. Additional preliminary data indicates that DNA methylation may also contribute to ectopic gene expression in mycosis fungoides (MF). MF represents more than half of CTCL cases, but malignant T cells in MF are limited to the skin. For several coordinately overexpressed and hypomethylated genes in SS, CpG hypomethylation was also increased in T cells eluted from MF tumors. Based on these observations, we hypothesize that altered DNA methylation supports pathogenic and ectopic gene expression in early and progressing MF/SS. This will be addressed with the following specific aims. Aim 1. Identify key epigenetic drivers of ectopic gene expression in SS. Paired transcriptome sequencing and genome-wide DNA methylation assays will map differential methylation and gene expression in SS T cells from the same subject to identify biomarkers of advanced disease. Aim 2. Identify SS-HEG that are useful biomarkers of disease severity in MF. DNA methylation profiles of SS and MF tumor-eluted T cells will be compared to identify SS-HEG differentially methylated in both lineages. Selected SS-HEG will be examined in lesional T cells eluted from early and late MF to identify stage-associated biomarkers. Aim 3. Identify SS-HEG that drive MF/SS progression. SS-HEG will be examined longitudinally in progressors and non-progressors. A novel facet of our approach will be to conduct RNA sequencing on both resting and activated T cells, so DNA methylation may be correlated to both basal gene expression and the permissiveness of activation. The conclusion of the proposed experiments will yield useful gene expression and DNA methylation biomarkers that could enable earlier diagnosis of CTCL in Veterans. This could prevent years of inappropriate therapy for Veterans suffering from CTCL. The research plan will also produce mechanistic insight into CTCL pathogenesis, and generate an experimental model for studies of skin-derived MF T cells.

基因组不稳定和表观遗传控制失调现在都被认为是癌症的标志，