Recent extensive studies on the genomic and molecular profiles of acute myeloid leukemia (AML) have expanded the treatment options, including, a range of compounds represented by fms-like tyrosine kinase 3 and isocitrate dehydrogenase 1/2 inhibitors. However, despite this progress, further treatments for AML are still required. Adenosine deaminase acting on RNA 1 (ADAR1) has been shown to play an important oncogenic role in many cancers, but its involvement in AML progression remains underexplored. In this study, we demonstrated that ADAR1 was overexpressed in AML and served as a crucial oncogenic target. Loss of ADAR1 inhibited the Wnt signaling pathway, blocked AML cell proliferation, and induced apoptosis. Importantly, we demonstrate that ADAR1, as an RNA-binding protein, interacts with pri-miR-766 independently of its editing function, regulating the maturation of miR-766-3p and enhancing the expression of WNT5B. Genetic inhibition or use of the ADAR1 inhibitor ZYS-1 significantly suppressed AML cell growth both in vitro and in vivo. Overall, these results elucidated the tumorigenic mechanism of ADAR1 and validated it as a potential drug target in AML.

最近对急性髓系白血病 （AML） 的基因组和分子特征的广泛研究扩大了治疗选择，包括以 fms 样酪氨酸激酶 3 和异柠檬酸脱氢酶 1/2 抑制剂为代表的一系列化合物。然而，尽管取得了这些进展，但仍需要对 AML 进行进一步治疗。作用于 RNA 1 的腺苷脱氨酶 （ADAR1） 已被证明在许多癌症中起着重要的致癌作用，但其参与 AML 进展仍未得到充分探索。在这项研究中，我们证明了 ADAR1 在 AML 中过表达，并且是一个关键的致癌靶点。ADAR1 缺失抑制 Wnt 信号通路，阻断 AML 细胞增殖，诱导细胞凋亡。重要的是，我们证明 ADAR1 作为一种 RNA 结合蛋白，与 pri-miR-766 相互作用，独立于其编辑功能，调节 miR-766-3p 的成熟并增强 WNT5B 的表达。遗传抑制或使用 ADAR1 抑制剂 ZYS-1 在体外和体内均显著抑制 AML 细胞生长。总体而言，这些结果阐明了 ADAR1 的致瘤机制，并验证了其作为 AML 的潜在药物靶点。