# Epigenetic Regulation of Differentially Expressed Genes in Cutaneous T Cell Lymphoma

> **NIH VA I01** · CENTRAL ARKANSAS VETERANS HLTHCARE SYS · 2022 · —

## Abstract

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...

## Key facts

- **NIH application ID:** 10490348
- **Project number:** 5I01CX001895-03
- **Recipient organization:** CENTRAL ARKANSAS VETERANS HLTHCARE SYS
- **Principal Investigator:** HENRY Keung WONG
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10490348

## Citation

> US National Institutes of Health, RePORTER application 10490348, Epigenetic Regulation of Differentially Expressed Genes in Cutaneous T Cell Lymphoma (5I01CX001895-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10490348. Licensed CC0.

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