Ministry of Education (MOE) Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou, China.
Hematology and Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Blood. 2022 Feb 17;139(7):1052-1065. doi: 10.1182/blood.2021013579.
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.
人类 T 细胞白血病病毒 1（HTLV-1）可引起成人 T 细胞白血病（ATL），但其起始的机制仍不清楚。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 的缺失完全阻断了 HTLV-1 癌蛋白 Tax 在小鼠中诱导的 T 细胞白血病发生，而 ORP4L 在 T 细胞中的表达则导致了小鼠的 T 细胞白血病，这表明 ORP4L 的致癌特性和前提促进了 T 细胞白血病的发生。为了深入了解分子机制，我们发现 HTLV-1 引起的 miR-31 的缺失导致了 T 细胞中 ORP4L 的表达。ORP4L 与 PI3Kδ 相互作用，促进 PI(3,4,5)P3 的产生，导致 AKT 的过度激活；NF-κB 依赖性、p53 失活诱导的原癌基因表达；以及 T 细胞白血病的发生。一致地，ORP4L 的缺失消除了患者来源的异种移植 ATL 模型中的人 ATL 细胞。这些结果揭示了 HTLV-1 导致 T 细胞恶化的一种合理机制，可作为治疗靶点。
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