Mitochondrial metabolism as a potential therapeutic target in myeloid leukaemia.
Mitochondrial metabolism as a potential therapeutic target in myeloid leukaemia.
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DOI：
10.1038/s41375-021-01416-w
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发表时间：
2022-01
期刊：
影响因子：
11.4
通讯作者：
Helgason GV
中科院分区：
文献类型：
--
作者：
de Beauchamp L;Himonas E;Helgason GV
虽然对慢性和急性髓性白血病（CML和AML）基因组畸变的理解使这些疾病的治疗方法得以发展，但局限性仍然存在。当观察导致白血病患者疾病复发的治疗耐药频率时，这些局限性变得明显。关于白血病细胞的基本生物学的关键问题，如它们的代谢依赖性，仍然没有得到解决。尽管大多数白血病细胞在初始治疗期间被杀死，但由于可能导致治疗抗性的各种机制，包括细胞代谢适应，持续性白血病干细胞（LSC）和治疗抗性细胞仍然没有被当前治疗根除。事实上，最近的研究表明，LSC和治疗抗性细胞依赖于线粒体代谢，因此使它们对线粒体氧化磷酸化（OXPHOS）的抑制敏感。因此，在白血病细胞中重新布线的能量代谢现在被认为是一个有吸引力的治疗靶点，并且该过程的重要性在各种血液恶性肿瘤中越来越被认识到。因此，识别和靶向耐药白血病细胞中的异常代谢是开发白血病新治疗选择的必要和相关策略。在这篇综述中，我们提出了一个详细的概述，目前的实验证据白血病细胞如何代谢重新布线，更具体地说，在LSC和治疗耐药细胞的重要性，以及目前的药物可用于靶向这一过程的最新研究。我们强调，揭示特定的能量代谢依赖性将指导确定新的和更有针对性的治疗策略的骨髓性白血病。
While the understanding of the genomic aberrations that underpin chronic and acute myeloid leukaemia (CML and AML) has allowed the development of therapies for these diseases, limitations remain. These become apparent when looking at the frequency of treatment resistance leading to disease relapse in leukaemia patients. Key questions regarding the fundamental biology of the leukaemic cells, such as their metabolic dependencies, are still unresolved. Even though a majority of leukaemic cells are killed during initial treatment, persistent leukaemic stem cells (LSCs) and therapy-resistant cells are still not eradicated with current treatments, due to various mechanisms that may contribute to therapy resistance, including cellular metabolic adaptations. In fact, recent studies have shown that LSCs and treatment-resistant cells are dependent on mitochondrial metabolism, hence rendering them sensitive to inhibition of mitochondrial oxidative phosphorylation (OXPHOS). As a result, rewired energy metabolism in leukaemic cells is now considered an attractive therapeutic target and the significance of this process is increasingly being recognised in various haematological malignancies. Therefore, identifying and targeting aberrant metabolism in drug-resistant leukaemic cells is an imperative and a relevant strategy for the development of new therapeutic options in leukaemia. In this review, we present a detailed overview of the most recent studies that present experimental evidence on how leukaemic cells can metabolically rewire, more specifically the importance of OXPHOS in LSCs and treatment-resistant cells, and the current drugs available to target this process. We highlight that uncovering specific energy metabolism dependencies will guide the identification of new and more targeted therapeutic strategies for myeloid leukaemia.
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