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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 targeting  LDHA  may be a potential strategy to improve T‐ALL outcomes. The current study was conducted to investigate the antileukemic effect of  LDHA  gene‐targeting treatment on T‐ALL and the underlying molecular mechanism.    Methods  Primary T‐ALL cell lines Jurkat and DU528 were treated with the  LDH  inhibitor 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 evaluate  ROS  production after T‐ALL cells were treated with oxamate. A T‐ALL transgenic zebrafish model with  LDHA  gene 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 of  LDHA  gene 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 stimulated  ROS  production (all  P  < 0.001). Blocking  LDHA  significantly decreased the gene and protein expression of  c‐Myc , as well as the levels of phosphorylated serine/threonine kinase (AKT) and glycogen synthase kinase 3 beta (GSK‐3β) in the phosphatidylinositol 3′‐kinase (PI3K) signaling pathway.  LDHA  gene knockdown delayed disease progression and down‐regulated  c‐Myc  mRNA and protein expression in T‐ALL transgenic zebrafish.    Conclusion  Targeting  LDHA  exerted an antileukemic effect on T‐ALL, representing a potential strategy for T‐ALL treatment.

Targeting lactate dehydrogenase A ( LDHA ) exerts antileukemic effects on T‐cell acute lymphoblastic leukemia