Haematology Department, Calvary Mater Hospital, Newcastle, NSW 2298, Australia.
Cancer Signalling Research Group, School of Biomedical Sciences & Pharmacy, Faculty of Health & Medicine, University of Newcastle, Callaghan, NSW 2308, Australia.
Int J Mol Sci. 2019 Nov 28;20(23):6003. doi: 10.3390/ijms20236003.
Acute myeloid leukaemia (AML) is an aggressive haematological malignancy with a poor overall survival. Reactive oxygen species (ROS) have been shown to be elevated in a wide range of cancers including AML. Whilst previously thought to be mere by-products of cellular metabolism, it is now clear that ROS modulate the function of signalling proteins through oxidation of critical cysteine residues. In this way, ROS have been shown to regulate normal haematopoiesis as well as promote leukaemogenesis in AML. In addition, ROS promote genomic instability by damaging DNA, which promotes chemotherapy resistance. The source of ROS in AML appears to be derived from members of the "NOX family" of NADPH oxidases. Most studies link NOX-derived ROS to activating mutations in the Fms-like tyrosine kinase 3 (FLT3) and Ras-related C3 botulinum toxin substrate (Ras). Targeting ROS through either ROS induction or ROS inhibition provides a novel therapeutic target in AML. In this review, we summarise the role of ROS in normal haematopoiesis and in AML. We also explore the current treatments that modulate ROS levels in AML and discuss emerging drug targets based on pre-clinical work.
急性髓系白血病（AML）是一种侵袭性血液系统恶性肿瘤，整体存活率较差。大量研究表明，活性氧（ROS）在包括 AML 在内的多种癌症中升高。尽管之前认为 ROS 仅仅是细胞代谢的副产物，但现在清楚的是，ROS 通过氧化关键半胱氨酸残基来调节信号蛋白的功能。通过这种方式，ROS 不仅可以调节正常造血，还可以促进 AML 中的白血病发生。此外，ROS 通过破坏 DNA 促进基因组不稳定性，从而导致化疗耐药。AML 中 ROS 的来源似乎来自 NADPH 氧化酶的“NOX 家族”成员。大多数研究将 NOX 衍生的 ROS 与 Fms 样酪氨酸激酶 3（FLT3）和 Ras 相关 C3 肉毒杆菌毒素底物（Ras）中的激活突变联系起来。通过 ROS 诱导或 ROS 抑制靶向 ROS 为 AML 提供了一个新的治疗靶点。在这篇综述中，我们总结了 ROS 在正常造血和 AML 中的作用。我们还探讨了目前调节 AML 中 ROS 水平的治疗方法，并根据临床前工作讨论了新的药物靶点。
