1,5-Anhydroglucitol promotes pre-B acute lymphocytic leukemia progression by driving glycolysis and reactive oxygen species formation

Abstract

Background Precursor B-cell acute lymphoblastic leukemia (pre-B ALL) is the most common hematological malignancy in children. Cellular metabolic reorganization is closely related to the progression and treatment of leukemia. We found that the level of 1,5-anhydroglucitol (1,5-AG), which is structurally similar to glucose, was elevated in children with pre-B ALL. However, the effect of 1,5-AG on pre-B ALL was unclear. Here, we aimed to reveal the roles and mechanisms of 1,5-AG in pre-B ALL progression. Methods The peripheral blood plasma level of children with initial diagnosis of pre-B ALL and that of healthy children was measured using untargeted metabolomic analysis. Cell Counting Kit-8 assay, RNA sequencing, siRNA transfection, real-time quantitative PCR, and western blot were performed using pre-B ALL cell lines Reh and HAL-01. Cell cycle, cell apoptosis, ROS levels, and the positivity rate of CD19 were assessed using flow cytometry. Oxygen consumption rates and extracellular acidification rate were measured using XFe24 Extracellular Flux Analyzer. The lactate and nicotinamide adenine dinucleotide phosphate levels were measured using kits. The effect of 1,5-AG on pre-B ALL progression was verified using the In Vivo Imaging System in a xenotransplantation leukemia model. Results We confirmed that 1,5-AG promoted the proliferation, viability, and intracellular glycolysis of pre-B ALL cells. Mechanistically, 1,5-AG promotes glycolysis while inhibiting mitochondrial respiration by upregulating pyruvate dehydrogenase kinase 4 (PDK4). Furthermore, high levels of intracellular glycolysis promote pre-B ALL progression by activating the reactive oxygen species (ROS)-dependent mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway. Conversely, N-acetylcysteine or vitamin C, an antioxidant, effectively inhibited 1,5-AG-mediated progression of leukemia cells. Conclusions Our study reveals a previously undiscovered role of 1,5-AG in pre-B ALL, which contributes to an in-depth understanding of anaerobic glycolysis in the progression of pre-B ALL and provides new targets for the clinical treatment of pre-B ALL.

Cancer Metabolism: The Role of ROS in DNA Damage and Induction of Apoptosis in Cancer Cells

“…The rapid uptake of glucose is accompanied by an increased rate of glycolysis. In precursor B-cell acute lymphoblastic leukemia cells, the glucose analog 1,5-anhydroglucitol interrupts mitochondrial respiration by up-regulating pyruvate dehydrogenase kinase 4 (PDK4), thereby increasing the rate of glycolysis, and enhanced glycolysis leads to oxidative stress in tumor cells by increasing ROS levels [ 76 , 77 ]. Additionally, the decreased O 2 − level under hypoxia conditions inhibits the AMP-activated protein kinase (AMPK) activation and shifts metabolism from glycolysis to oxidative phosphorylation [ 78 ].…”

“…It promotes the proliferation of acute myeloid leukemia by up-regulating the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3), a key glycolytic regulator [ 92 ]. Furthermore, elevated glycolysis levels can promote the progression of precursor B-cell acute lymphocytic leukemia (pre-B AML) by activating MAPK/ERK pathways by increasing intracellular ROS levels [ 77 ]. The above research studies have shown that increased ROS accumulation can promote tumor progression through a variety of signaling pathways ( Figure 2 ).…”

The relationship between serum 1,5-anhydroglucitol and adverse outcomes in acute coronary syndrome with and without chronic kidney disease patients

“…Blood glucose fluctuation could potentially have a crucial role in the advancement of coronary heart disease (CHD) patients [ 7 ]. 1,5-anhydroglucitol (1,5-AG) levels drop quickly with urinary glucose excretion, indicating glucose status over the past two weeks [ 8 ]. Recent research have found that 1,5-AG may provide a meaningful addition to glycosylated hemoglobin (Hb1Ac) testing, indicating short-term blood glucose status in contrast to traditional glucose markers [ 9 ].…”