Targeted zinc-finger repressors to the oncogenic HBZ gene inhibit adult T-cell leukemia (ATL) proliferation.
Targeted zinc-finger repressors to the oncogenic HBZ gene inhibit adult T-cell leukemia (ATL) proliferation.
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作者：
人类嗜t淋巴病毒I型（HTLV-I）感染CD4+ t细胞，导致患者的潜伏性终身感染。致癌病毒因子之间的串扰导致宿主细胞转化为侵袭性癌症，成人t细胞白血病/淋巴瘤（ATL）。ATL预后不良，目前尚无有效的治疗方法，迫切需要开发新的治疗策略。最近研究ATL机制的证据强调了病毒反义基因HTLV-I bZIP因子（HBZ）作为肿瘤驱动因子和潜在的治疗靶点。在这项工作中，设计了一系列锌指蛋白（ZFP）阻遏物，以HTLV-I启动子为靶点，该启动子驱动HBZ在高度保守位点的表达，覆盖了广泛的HTLV-I基因型。ZFPs可以有效抑制HBZ的表达，导致患者来源的ATL细胞系的增殖和活力显著降低，并诱导细胞周期阻滞和凋亡。这些数据鼓励开发这种新的ZFP策略作为抑制ATL分子驱动的靶向模式，这可能是侵袭性HTLV-I相关恶性肿瘤的下一代治疗方法。一种靶向HTLV-I的3 ' -LTR启动子的锌指蛋白（ZFP）抑制因子抑制HBZ癌基因，导致成人t细胞白血病（ATL）的抗增殖作用。
Human T-lymphotropic virus type I (HTLV-I) infects CD4+ T-cells resulting in a latent, life-long infection in patients. Crosstalk between oncogenic viral factors results in the transformation of the host cell into an aggressive cancer, adult T-cell leukemia/lymphoma (ATL). ATL has a poor prognosis with no currently available effective treatments, urging the development of novel therapeutic strategies. Recent evidence exploring those mechanisms contributing to ATL highlights the viral anti-sense gene HTLV-I bZIP factor (HBZ) as a tumor driver and a potential therapeutic target. In this work, a series of zinc-finger protein (ZFP) repressors were designed to target within the HTLV-I promoter that drives HBZ expression at highly conserved sites covering a wide range of HTLV-I genotypes. ZFPs were identified that potently suppressed HBZ expression and resulted in a significant reduction in the proliferation and viability of a patient-derived ATL cell line with the induction of cell cycle arrest and apoptosis. These data encourage the development of this novel ZFP strategy as a targeted modality to inhibit the molecular driver of ATL, a possible next-generation therapeutic for aggressive HTLV-I associated malignancies. A targeted zinc-finger protein (ZFP) repressor to the 3′-LTR promoter of HTLV-I suppresses the HBZ oncogene resulting in anti-proliferative effects in adult T-cell leukemia (ATL).
影响因子：
3.3
作者：
Tanaka Y;Mizuguchi M;Takahashi Y;Fujii H;Tanaka R;Fukushima T;Tomoyose T;Ansari AA;Nakamura M
通讯作者：
Nakamura M