Targeting Lactate Dehydrogenase A (Ldha) Exerts Antileukemic Effects On T-Cell Acute Lymphoblastic Leukemia

Background T-cell acute lymphoblastic leukemia (T-ALL) is an uncommon and aggressive subtype of acute lymphoblastic leukemia (ALL). In the serum of T-ALL patients, the activity of lactate dehydrogenase A (LDHA) is increased. We proposed that targetingLDHAmay be a potential strategy to improve T-ALL outcomes. The current study was conducted to investigate the antileukemic effect ofLDHAgene-targeting treatment on T-ALL and the underlying molecular mechanism. Methods Primary T-ALL cell lines Jurkat and DU528 were treated with theLDHinhibitor oxamate. MTT, colony formation, apoptosis, and cell cycle assays were performed to investigate the effects of oxamate on T-ALL cells. Quantitative real-time PCR (qPCR) and Western blotting analyses were applied to determine the related signaling pathways. A mitochondrial reactive oxygen species (ROS) assay was performed to evaluateROSproduction after T-ALL cells were treated with oxamate. A T-ALL transgenic zebrafish model withLDHAgene knockdown was established using CRISPR/Cas9 gene-editing technology, and then TUNEL, Western blotting, and T-ALL tumor progression analyses were conducted to investigate the effects ofLDHAgene knockdown on T-ALL transgenic zebrafish. Results Oxamate significantly inhibited proliferation and induced apoptosis of Jurkat and DU528 cells. It also arrested Jurkat and DU528 cells in G0/G1 phase and stimulatedROSproduction (allP < 0.001). BlockingLDHAsignificantly decreased the gene and protein expression ofc-Myc, as well as the levels of phosphorylated serine/threonine kinase (AKT) and glycogen synthase kinase 3 beta (GSK-3 beta) in the phosphatidylinositol 3 '-kinase (PI3K) signaling pathway.LDHAgene knockdown delayed disease progression and down-regulatedc-MycmRNA and protein expression in T-ALL transgenic zebrafish. Conclusion TargetingLDHAexerted an antileukemic effect on T-ALL, representing a potential strategy for T-ALL treatment.