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.
背景/目的：本研究通过分析外周血单个核细胞基因表达变化，探讨组蛋白去乙酰化酶抑制剂罗米地辛对皮肤T细胞淋巴瘤患者的连续治疗效应。方法：基于一位治疗反应显著的患者在12个月治疗周期内的数据，我们构建了恶性细胞预测因子——一种与循环恶性细胞数量减少相关的基因特征谱。结果：该预测因子在患者治疗终止9个月后的复发样本中及独立CTCL患者样本集中均得到有效验证。结论：该基因集合包含新型CTCL标志物，包括淋巴细胞通常不表达的膜相关蛋白。其中部分标志物在流式细胞术未检出的残留恶性细胞中仍可检测，该残留细胞来自10个月后复发患者的缓解期样本。我们鉴定出与渐进治疗效应相关的转录调控因子、微小RNA及甲基化模式亚群，揭示了恶性细胞中转录失调的潜在机制及功能影响。研究证实转录激活因子HLF在恶性细胞中过表达，而转录抑制因子兼免疫调节剂NFIL3表达下调，二者共同调控CTCL特异性基因。
肿瘤(癌症)患者之家