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.

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.

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