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

Cancer Communications

article

Haizhi Yu¹  Fanjie Gong¹  Zhihua Wang¹  Heng Li¹  Hongling Peng¹  Guangsen Zhang¹  Yafei Yin¹  Yifang Yi¹  Zhao Cheng¹  Wenyong Kuang⁷  Ruijuan Li¹  Haiying Zhong¹  Yajuan Cui¹  Lingli Yuan¹ 

[1] Department of Hematology, the Second Xiangya Hospital, Central South University;Institute of Hematology, Central South University;Department of Respiratory and Critical Medicine, NHC Key Laboratory of Pulmonary Immune-related Diseases, People's Hospital of Guizhou University, Guizhou Provincial People's Hospital;Hunan Key Laboratory of Tumor Models and Individualized Medicine;Department of Hematology, Xiangtan Central Hospital;Department of Hematology, Hunan Provincial People's Hospital, the First Affiliated Hospital of Hunan Normal University;Department of Hematology, Hunan Children's Hospital

关键词: CRISPR/Cas9 gene-editing;    LDHA;    oxamate;    T-cell lymphoblastic leukemia;    transgenic zebrafish model;   

DOI  :  10.1002/cac2.12080

学科分类：社会科学、人文和艺术（综合）

来源: Springer

【 摘 要 】

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.

【 授权许可】

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