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引用次数: 0
摘要
最近发现了急性髓性白血病(AML)特有的线粒体代谢依赖性,表明代谢酶可调节 AML 基因表达,控制细胞分化和干性。这些线粒体代谢适应性与潜在的基因组异常无关,是导致化疗耐药性和复发的原因之一。线粒体的改变也会导致急性髓细胞代谢的脆弱性,其代谢的特点是依赖氧化磷酸化、脂肪酸氧化、活性氧(ROS)产生和线粒体动力学。目前正在研究急性髓细胞性白血病细胞和白血病干细胞的线粒体特性,重点是新陈代谢、信号转导、线粒体呼吸、ROS 生成和有丝分裂。此外,线粒体靶向药物已在临床试验中显示出良好的效果。本文概述了针对线粒体相关分子和代谢途径的药物的临床前和临床试验的最新研究结果,以及这些药物与现有化疗药物联合使用的疗效。
Mitochondrial metabolic dependencies characteristic of acute myeloid leukemia (AML) have recently been identified, demonstrating that metabolic enzymes regulate AML gene expression and control cell differentiation and stemness. These mitochondrial metabolic adaptations occur independently of underlying genomic abnormalities and contribute to chemotherapy resistance and relapse. Mitochondrial alterations also lead to metabolic vulnerability of AML cells, whose metabolism is characterized by dependence on oxidative phosphorylation, fatty acid oxidation, reactive oxygen species (ROS) production, and mitochondrial dynamics. Currently, mitochondrial properties of AML cells and leukemia stem cells are being investigated, focusing on metabolism, signal transduction, mitochondrial respiration, ROS generation, and mitophagy. In addition, mitochondria-targeted agents have shown promising results in clinical trials. This paper outlines recent findings from preclinical and clinical trials on the utility of agents targeting mitochondria-related molecules and metabolic pathways and their efficacy in combination with existing chemotherapies.