# Cutaneous T-Cell Lymphoma: Yin-Yang Effects of Transcription Factors HLF and NFIL3 in Regulation of Malignant T-Cell Markers in the Context of HDAC Inhibitor Romidepsin Treatment

## TL;DR

This study explores how romidepsin treatment affects gene expression in cutaneous T-cell lymphoma patients, identifying new markers and mechanisms of disease regulation.

## Contribution

The study identifies novel malignant cell markers and the regulatory roles of HLF and NFIL3 in CTCL under romidepsin treatment.

## Key findings

- A malignant cell predictor (MCP) was identified and validated in CTCL patient samples.
- HLF and NFIL3 were found to regulate CTCL-specific genes during romidepsin treatment.
- New surface markers detectable in residual disease were identified.

## Abstract

The drug romidepsin, which is known to regulate gene expression, has been shown to be an effective treatment in a subset of patients with cutaneous T-cell lymphoma (CTCL). We examined gene expression changes that occurred through repeated romidepsin treatments using carefully collected blood cell samples from treated CTCL patients. Focusing on data from a highly responsive CTCL patient through 12 months of treatment, including a period free from disease, we identified new markers that are characteristic of the malignant cells and difficult-to-detect residual disease. We identified effected cell functions and potential mechanisms of dysregulation through changes in miRNA expression and DNA methylation patterns. We also found a significant impact of transcriptional regulators HLF (activator) and NFIL3 (suppressor) that control the expression of malignant-specific genes. We report new surface markers for the malignant cells, including markers identifiable in residual disease, and new potential therapeutic targets.

Background/Objectives: We examined the in vivo effects of successive treatments with the histone deacetylase (HDAC) inhibitor romidepsin in patients with cutaneous T-cell lymphoma (CTCL), using changes in gene expression in peripheral blood mononuclear cells (PBMCs). Methods: Exploiting data from a highly responsive CTCL patient through 12 months of treatment, we identified a malignant cell predictor (MCP), a gene signature associated with the diminishing numbers of circulating malignant cells. Results: The MCP was successfully validated in the patient’s relapse sample 9 months after treatment was terminated and via an independent set of CTCL patient samples. Conclusions: The MCP set of genes contained novel CTCL markers, including membrane-associated proteins not normally expressed in lymphocytes. A subclass of those markers was also detectable in residual malignant cells undetected by flow cytometry in remission samples from a patient who relapsed 10 months later. We identified a subset of transcriptional regulators, miRNAs and methylation patterns associated with the effect of progressive treatments revealing potential mechanisms of transcriptional dysregulation and functional effects in the malignant cells. We demonstrate a role for transcriptional activator HLF, over-expressed in malignant cells, and downregulated transcriptional-suppressor and immune-modulator NFIL3, as regulators of CTCL-specific genes.