Abstract
Acute lymphoblastic leukemia (ALL) is a hematological malignancy originating from B- or T-lymphoid progenitor cells. Recent studies have shown that redox dysregulation caused by overproduction of reactive oxygen species (ROS) has an important role in the development and progression of leukemia. The application of pro-oxidant therapy, which targets redox dysregulation, has achieved satisfactory results in alleviating the conditions of and improving the survival rate for patients with ALL. However, drug resistance and side effects are two major challenges that must be addressed in pro-oxidant therapy. Oxidative stress can activate a variety of antioxidant mechanisms to help leukemia cells escape the damage caused by pro-oxidant drugs and develop drug resistance. Hematopoietic stem cells (HSCs) are extremely sensitive to oxidative stress due to their low levels of differentiation, and the use of pro-oxidant drugs inevitably causes damage to HSCs and may even cause severe bone marrow suppression. In this article, we reviewed research progress regarding the generation and regulation of ROS in normal HSCs and ALL cells as well as the impact of ROS on the biological behavior and fate of cells. An in-depth understanding of the regulatory mechanisms of redox homeostasis in normal and malignant HSCs is conducive to the formulation of rational targeted treatment plans to effectively reduce oxidative damage to normal HSCs while eradicating ALL cells.
Highlights
Acute lymphoblastic leukemia (ALL) is a type of acute leukemia that mainly manifests as abnormal clonal proliferation of naive or mature T and B lymphocytes and their infiltration of bone marrow (BM), blood, or other organs and tissues, causing BM hematopoietic dysfunction and immune dysfunction
Through the establishment of an ETV6-RUNX1 transgenic mouse model, Kantner et al found that no notable hematopoietic abnormalities were observed in mice, the reactive oxygen species (ROS) level in B cells increased, and DNA damage increased. These results indicated that expression of the oncogene ETV6-RUNX1 might trigger the second strike by enhancing ROS production, eventually inducing leukemic transformation [59]
In addition to the drug resistance caused by redox adaptation, another thorny issue that has been affecting the efficacy of pro-oxidant therapy for leukemia is the side effects of pro-oxidant drugs on normal cells
Summary
Acute lymphoblastic leukemia (ALL) is a type of acute leukemia that mainly manifests as abnormal clonal proliferation of naive or mature T and B lymphocytes and their infiltration of bone marrow (BM), blood, or other organs and tissues, causing BM hematopoietic dysfunction and immune dysfunction. Leukemia cells can modify the BM niche into a leukemia growth-permissive and normal hematopoiesis-suppressive leukemia niche, rendering the BM niche a sanctuary for leukemia cells to avoid damage from prooxidant agents [3,4,5]. These are important causes of leukemia cells’ resistance to pro-oxidant drugs and ALL relapse. Strengthening the cytotoxic effect of ROS on tumor cells while avoiding oxidative damage to normal HSCs has become an important issue in pro-oxidant therapy for leukemia
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