Department of Internal Medicine, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.
Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.
Blood Cancer J. 2023 May 3;13(1):67. doi: 10.1038/s41408-023-00841-7.
Adult T cell leukemia/lymphoma (ATL) is an aggressive malignancy secondary to chronic infection with human T cell leukemia virus type 1 (HTLV-1). The viral oncoprotein Tax initiates T cell transformation through activation of critical cellular pathways, including NF-κB. Unexpectedly, Tax protein is not detectable in most ATL cells, in contrast to the HTLV-1 HBZ protein which antagonizes Tax effects. Here, we demonstrate that primary ATL cells from patients with acute or chronic ATL express very low levels of Tax mRNA and protein. Critically, survival of these primary ATL cells is dependent on continued Tax expression. Mechanistically, Tax extinction results in reversal of NF-κB activation, P53/PML activation and apoptosis. Tax drives interleukin-10 (IL-10) expression and recombinant IL-10 rescues the survival of tax-depleted primary ATL cells. These results demonstrate the critical role of continued Tax and IL-10 expression for the survival of primary ATL cells, highlighting their relevance as therapeutic targets.
成人 T 细胞白血病/淋巴瘤（ATL）是一种侵袭性恶性肿瘤，继发于人类 T 细胞白血病病毒 1 型（HTLV-1）的慢性感染。病毒癌蛋白 Tax 通过激活关键细胞途径，包括 NF-κB，引发 T 细胞转化。出乎意料的是，与拮抗 Tax 作用的 HTLV-1 HBZ 蛋白相反，大多数 ATL 细胞中检测不到 Tax 蛋白。在这里，我们证明来自急性或慢性 ATL 患者的原发性 ATL 细胞表达极低水平的 Tax mRNA 和蛋白。至关重要的是，这些原发性 ATL 细胞的存活依赖于持续的 Tax 表达。从机制上讲，Tax 的消失导致 NF-κB 激活、P53/PML 激活和细胞凋亡的逆转。Tax 驱动白细胞介素 10（IL-10）的表达，重组 IL-10 可挽救 Tax 耗尽的原发性 ATL 细胞的存活。这些结果表明持续的 Tax 和 IL-10 表达对原发性 ATL 细胞存活的关键作用，突出了它们作为治疗靶点的相关性。
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