Oxidative resistance of leukemic stem cells and oxidative damage to hematopoietic stem cells under pro-oxidative therapy.

Leukemic stem cells (LSCs) and hematopoietic stem cells (HSCs) are both dependent on the hypoxic bone marrow (BM) microenvironment (also known as the BM niche). There is always fierce competition between the two types of cells, and the former exhibits a greater competitive advantage than the latter via multiple mechanisms. Under hypoxia, the dynamic balance between the generation and clearing of intracellular reactive oxygen species (ROS) is conducive to maintaining a quiescent state of cells. Quiescent LSCs can reside well in the BM niche, avoiding attack by chemotherapeutic agents, which is the cause of chemotherapeutic resistance and relapse in leukemia. HSCs acquire energy mainly through anaerobic glycolysis, whereas LSCs achieve energy metabolism largely through mitochondrial oxidative respiration. Mitochondria are the primary site of ROS generation. Thus, in theory, mitochondria-mediated respiration will cause an increase in ROS generation in LSCs and a higher intracellular oxidative stress level. The sensitivity of the cells to pro-oxidant drugs increases as well, which allows for the selective clearing of LSCs by pro-oxidative therapy. However, HSCs are also highly sensitive to changes in ROS levels, and the toxic effects of pro-oxidant drugs on HSCs poses a major challenge to pro-oxidative therapy in leukemia. Given the above facts, we reviewed studies on the oxidative resistance of LSCs and the oxidative damage to HSCs under pro-oxidative therapy. An in-depth investigation into the oxidative stress status and regulatory mechanisms of LSCs and HSCs in hypoxic environments will promote our understanding of the survival strategy employed by LSCs and the mechanism of the oxidative damage to HSCs in the BM niche, thus facilitating individualized treatment of leukemia patients and helping eliminate LSCs without disturbing normal hematopoietic cells.