State Key Laboratory of Pharmaceutical Biotechnology, Department of Rheumatology and Immunology, The Affiliated Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, School of Life Sciences, Nanjing University, Nanjing, 210023, China.
State Key Laboratory of Pharmaceutical Biotechnology, Department of Rheumatology and Immunology, The Affiliated Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, School of Life Sciences, Nanjing University, Nanjing, 210023, China.
Exp Cell Res. 2020 Oct 15;395(2):112213. doi: 10.1016/j.yexcr.2020.112213. Epub 2020 Aug 3.
Extensive literature has demonstrated that acute myeloid leukaemia (AML) cells show enhanced mitochondrial biogenesis and increased reliance on oxidative phosphorylation (OXPHOS) compared with normal hematopoietic progenitors, and one hallmark of AML leukaemia blasts is myeloid differentiation blockade. However, relatively few reports have linked these processes. Recent studies have indicated that therapies that overcome differentiation arrest represent an effective treatment strategy. Here, we identified that the disruption of the mitochondrial mass and energy metabolism promotes leukaemia cellular myeloid differentiation. In this study, we showed that acute monocytic leukaemia (AML-M5) cells package mitochondria in microvesicles (MVs) when MVs shed from membranes. Additionally, during myeloid differentiation, we report for the first time that differentiated leukaemia cells release more MVs than undifferentiated leukaemia cells. Targeting the formation of MVs using a specific inhibitor (Y-27632) restrained myeloid differentiation, suggesting that the increased release level of MVs plays an important role in regulating myeloid differentiation. Furthermore, the intracellular mitochondria and ATP levels were decreased after leukaemia cells overcame the differentiation blockade. Moreover, rotenone, which is used to inhibit the respiratory chain and ATP production, had a strong effect on myeloid differentiation in monocytic leukaemia cells. Collectively, these studies uncovered the relationship between mitochondrial function and myeloid differentiation and may provide more insight into the diagnosis and treatment of AML.
大量文献表明，与正常造血祖细胞相比，急性髓系白血病（AML）细胞表现出增强的线粒体生物发生和对氧化磷酸化（OXPHOS）的依赖性增加，而 AML 白血病细胞的一个标志是髓样分化阻滞。然而，相对较少的报道将这些过程联系起来。最近的研究表明，克服分化阻滞的治疗方法代表了一种有效的治疗策略。在这里，我们发现破坏线粒体质量和能量代谢会促进白血病细胞的髓样分化。在这项研究中，我们表明急性单核细胞白血病（AML-M5）细胞在从膜上脱落的微泡（MVs）中包装线粒体。此外，在髓样分化过程中，我们首次报道分化的白血病细胞比未分化的白血病细胞释放更多的 MV。使用特定抑制剂（Y-27632）靶向 MV 的形成会抑制髓样分化，这表明 MV 释放水平的增加在调节髓样分化中起着重要作用。此外，白血病细胞克服分化阻滞后，细胞内线粒体和 ATP 水平下降。此外，用于抑制呼吸链和 ATP 产生的鱼藤酮对单核细胞白血病细胞的髓样分化有很强的作用。总之，这些研究揭示了线粒体功能与髓样分化之间的关系，并可能为 AML 的诊断和治疗提供更多的见解。
