ATL response to arsenic/interferon therapy is triggered by SUMO/PML/RNF4-dependent Tax degradation
ATL response to arsenic/interferon therapy is triggered by SUMO/PML/RNF4-dependent Tax degradation
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DOI：
10.1182/blood-2014-04-572750
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发表时间：
2015-01-15
期刊：
影响因子：
20.3
通讯作者：
Bazarbachi, Ali
中科院分区：
文献类型：
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作者：
Dassouki, Zeina;Sahin, Umut;Bazarbachi, Ali
人类t细胞嗜淋巴病毒I型（HTLV-1） Tax转激活子在成人t细胞白血病/淋巴瘤（ATL）中启动转化，ATL是一种高度侵袭性的耐化疗恶性肿瘤。砷/干扰素组合触发Tax致癌蛋白降解，选择性诱导ATL细胞系凋亡，在Tax驱动的小鼠ATL或人类患者中具有显著的临床活性。然而，税收损失在ATL反应中的作用是有争议的，并且驱动降解的分子机制仍然难以捉摸。在这里，我们证明atl衍生或htlv -1转化的细胞依赖于连续的Tax表达，这表明Tax降解是对砷/干扰素联合治疗的临床反应的基础。后者促进早幼粒细胞白血病蛋白（PML）核体（NB）的形成和伴侣蛋白的募集。在砷/干扰素处理的HTLV-1转化或ATL细胞中，Tax被募集到NBs上，并被小泛素样修饰物（SUMO）2/3（而不是SUMO）2/3、RNF4泛素化和蛋白酶体依赖性降解所依赖的pml依赖的超泛素化。因此，砷/干扰素联合治疗通过降解ATL的Tax驱动因子来清除ATL，并且通过促进其他致病性sumoylated蛋白的降解，该方案可能具有更广泛的治疗价值。
The human T-cell lymphotropic virus type I (HTLV-1) Tax transactivator initiates transformation in adult T-cell leukemia/lymphoma (ATL), a highly aggressive chemotherapy-resistant malignancy. The arsenic/interferon combination, which triggers degradation of the Tax oncoprotein, selectively induces apoptosis of ATL cell lines and has significant clinical activity in Tax-driven murine ATL or human patients. However, the role of Tax loss in ATL response is disputed, and the molecular mechanisms driving degradation remain elusive. Here we demonstrate that ATL-derived or HTLV-1-transformed cells are dependent on continuous Tax expression, suggesting that Tax degradation underlies clinical responses to the arsenic/interferon combination. The latter enforces promyelocytic leukemia protein (PML) nuclear body (NB) formation and partner protein recruitment. In arsenic/interferon-treated HTLV-1 transformed or ATL cells, Tax is recruited onto NBs and undergoes PML-dependent hyper-sumoylation by small ubiquitin-like modifier (SUMO)2/3 but not SUMO1, ubiquitination by RNF4, and proteasome-dependent degradation. Thus, the arsenic/interferon combination clears ATL through degradation of its Tax driver, and this regimen could have broader therapeutic value by promoting degradation of other pathogenic sumoylated proteins.