Targeted zinc-finger repressors to the oncogenic HBZ gene inhibit adult T-cell leukemia (ATL) proliferation.

NAR Cancer Pub Date : 2023-01-11 eCollection Date: 2023-03-01 DOI:10.1093/narcan/zcac046
Tristan A Scott, Citradewi Soemardy, Roslyn M Ray, Kevin V Morris
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Abstract

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.

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致癌基因 HBZ 的靶向锌指抑制因子可抑制成人 T 细胞白血病(ATL)的增殖。
人类嗜 T 淋巴细胞病毒 I 型(HTLV-I)感染 CD4+ T 细胞,导致患者终身潜伏感染。致癌病毒因子之间的相互作用导致宿主细胞转变为一种侵袭性癌症--成人 T 细胞白血病/淋巴瘤(ATL)。ATL 的预后很差,目前还没有有效的治疗方法,因此需要开发新的治疗策略。最近有证据表明,病毒反义基因 HTLV-I bZIP 因子(HBZ)是导致 ATL 的机制之一,也是潜在的治疗靶点。在这项研究中,我们设计了一系列锌指蛋白(ZFP)抑制因子,靶向HTLV-I启动子中驱动HBZ表达的高度保守位点,这些位点涵盖了多种HTLV-I基因型。研究发现,ZFPs 能有效抑制 HBZ 的表达,并显著降低源自患者的 ATL 细胞系的增殖和存活率,诱导细胞周期停滞和凋亡。这些数据鼓励开发这种新型 ZFP 策略,作为抑制 ATL 分子驱动因素的靶向方法,这可能是治疗侵袭性 HTLV-I 相关恶性肿瘤的下一代疗法。
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