Department of Dermatology and Venereology, Peking University First Hospital, Beijing, China.
Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China.
Front Immunol. 2023 Dec 22;14:1282996. doi: 10.3389/fimmu.2023.1282996. eCollection 2023.
Cutaneous T cell lymphoma (CTCL) is a non-Hodgkin lymphoma characterized by skin infiltration of malignant T cells. The biological overlap between malignant T cells and their normal counterparts has brought obstacles in identifying tumor-specific features and mechanisms, limiting current knowledge of CTCL pathogenesis. Transcriptional dysregulation leading to abnormal gene expression profiles contributes to the initiation, progression and drug resistance of cancer. Therefore, we aimed to identify tumor-specific transcription factor underlying CTCL pathology.
We analyzed and validated the differentially expressed genes (DEGs) in malignant T cells based on single-cell sequencing data. Clinical relevance was evaluated based on progression-free survival and time to next treatment. To determine the functional importance, lentivirus-mediated gene knockdown was conducted in two CTCL cell lines Myla and H9. Cell survival was assessed by examining cell viability, colony-forming ability, tumor growth in xenograft models, apoptosis rate and cell-cycle distribution. RNA sequencing was employed to investigate the underlying mechanisms.
Activating transcription factor 5 (ATF5) was overexpressed in malignant T cells and positively correlated with poor treatment responses in CTCL patients. Mechanistically, ATF5 promoted the survival of malignant T cells partially through the PI3K/AKT/mTOR pathway, and imparted resistance to endoplasmic reticulum (ER) stress-induced apoptosis.
These findings revealed the tumor-specific overexpression of the transcription factor ATF5 with its underlying mechanisms in promoting tumor survival in CTCL, providing new insight into the understanding of CTCL's pathology.
皮肤 T 细胞淋巴瘤（CTCL）是一种非霍奇金淋巴瘤，其特征是恶性 T 细胞浸润皮肤。恶性 T 细胞与其正常对应物之间的生物学重叠给识别肿瘤特异性特征和机制带来了障碍，限制了对 CTCL 发病机制的现有认识。转录失调导致异常的基因表达谱，促成了癌症的发生、进展和耐药性。因此，我们旨在确定 CTCL 病理背后的肿瘤特异性转录因子。
我们基于单细胞测序数据分析和验证了恶性 T 细胞中的差异表达基因（DEGs）。根据无进展生存期和下一次治疗时间评估临床相关性。为了确定功能重要性，我们在两种 CTCL 细胞系 Myla 和 H9 中通过慢病毒介导的基因敲低进行了实验。通过检查细胞活力、集落形成能力、异种移植模型中的肿瘤生长、凋亡率和细胞周期分布来评估细胞存活情况。我们还进行了 RNA 测序以研究潜在机制。
激活转录因子 5（ATF5）在恶性 T 细胞中过表达，并与 CTCL 患者的不良治疗反应呈正相关。在机制上，ATF5 通过 PI3K/AKT/mTOR 途径部分促进恶性 T 细胞的存活，并赋予其对内质网（ER）应激诱导的细胞凋亡的耐药性。
这些发现揭示了转录因子 ATF5 在 CTCL 中促进肿瘤存活的肿瘤特异性过表达及其潜在机制，为深入了解 CTCL 的病理提供了新的见解。
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