皮肤T细胞淋巴瘤：在组蛋白去乙酰化酶抑制剂罗米地辛治疗背景下，转录因子HLF和NFIL3对恶性T细胞标志物调控的阴阳效应

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.

作者信息

Kossenkov Andrew V, Dawany Noor, Majumdar Sonali, Chang Celia, Nichols Calen, Wysocka Maria, Piekarz Richard, Showe Michael K, Bates Susan E, Rook Alain H, Kim Ellen J, Showe Louise C

机构信息

The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA.

Department of Dermatology, University of Pennsylvania, Philadelphia, PA 19104, USA.

出版信息

Cancers (Basel). 2025 Jul 17;17(14):2380. doi: 10.3390/cancers17142380.

DOI:10.3390/cancers17142380

PMID:40723261

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12293868/

Abstract

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.

摘要

背景/目的：我们利用外周血单核细胞（PBMC）中基因表达的变化，研究了组蛋白去乙酰化酶（HDAC）抑制剂罗米地辛连续治疗对皮肤T细胞淋巴瘤（CTCL）患者的体内影响。

方法

通过对一名反应高度敏感的CTCL患者进行12个月的治疗，我们确定了一个恶性细胞预测指标（MCP），这是一种与循环恶性细胞数量减少相关的基因特征。

结果

在治疗终止9个月后的患者复发样本中，以及通过一组独立的CTCL患者样本，成功验证了MCP。

结论

MCP基因集包含新的CTCL标志物，包括淋巴细胞中通常不表达的膜相关蛋白。在一名10个月后复发患者的缓解样本中，流式细胞术未检测到的残留恶性细胞中也可检测到这些标志物的一个亚类。我们确定了一组与渐进性治疗效果相关的转录调节因子、微小RNA（miRNA）和甲基化模式，揭示了恶性细胞中转录失调和功能影响的潜在机制。我们证明了在恶性细胞中过度表达的转录激活因子HLF以及下调的转录抑制因子和免疫调节因子NFIL3作为CTCL特异性基因调节因子的作用。