Human T-cell leukemia virus 1 (HTLV-1) causes adult T-cell leukemia (ATL), but the mechanism underlying its initiation remains elusive. In this study, ORP4L was expressed in ATL cells but not in normal T-cells. ORP4L ablation completely blocked T-cell leukemogenesis induced by the HTLV-1 oncoprotein Tax in mice, whereas engineering ORP4L expression in T-cells resulted in T-cell leukemia in mice, suggesting the oncogenic properties and prerequisite of ORP4L promote the initiation of T-cell leukemogenesis. For molecular insight, we found that loss of miR-31 caused by HTLV-1 induced ORP4L expression in T-cells. ORP4L interacts with PI3Kδ to promote PI(3,4,5)P3 generation, contributing to AKT hyperactivation; NF-κB-dependent, p53 inactivation-induced pro-oncogene expression; and T-cell leukemogenesis. Consistently, ORP4L ablation eliminates human ATL cells in patient-derived xenograft ATL models. These results reveal a plausible mechanism of T-cell deterioration by HTLV-1 that can be therapeutically targeted.

中文翻译：

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ORP4L 是诱导与人类 T 细胞白血病病毒 1 相关的 T 细胞白血病发生的先决条件。

人类 T 细胞白血病病毒 1 (HTLV-1) 会导致成人 T 细胞白血病 (ATL)，但其引发的机制仍然难以捉摸。在这项研究中，ORP4L 在 ATL 细胞中表达，但在正常 T 细胞中不表达。ORP4L 消融完全阻断了小鼠 HTLV-1 癌蛋白 Tax 诱导的 T 细胞白血病发生，而 T 细胞中的工程化 ORP4L 表达导致小鼠 T 细胞白血病，这表明 ORP4L 的致癌特性和先决条件促进了 T-细胞的启动。细胞白血病发生。对于分子洞察，我们发现由 HTLV-1 引起的 miR-31 缺失诱导 T 细胞中的 ORP4L 表达。ORP4L 与 PI3Kδ 相互作用，促进 PI(3,4,5)P3 生成，促进 AKT 过度激活；NF-κB 依赖性、p53 失活诱导的原癌基因表达；和 T 细胞白血病发生。始终如一，ORP4L 消融消除了源自患者的异种移植 ATL 模型中的人类 ATL 细胞。这些结果揭示了 HTLV-1 引起的 T 细胞退化的合理机制，可以作为治疗靶向。