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

查看全文 作　　者：Haizhi [1,2,3]Yu;Yafei [1,2,4]Yin;Yifang [1,2,5]Yi;Zhao [1,2]Cheng;Wenyong [6]Kuang;Ruijuan [1,2]Li;Haiying [1,2]Zhong;Yajuan [1,2]Cui;Lingli [1,2]Yuan;Fanjie [1,2]Gong;Zhihua [1,2]Wang;Heng [1,2]Li;Hongling [1,2,7]Peng;Guangsen [1,2]Zhang

机构地区：[1]Department of Hematology,the Second Xiangya Hospital,Central South University,Changsha,Hunan 410011,P.R.China;[2]Institute of Hematology,Central South University,Changsha,Hunan 410011,P.R.China;[3]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,Guiyang,Guizhou 550002,P.R.China;[4]Department of Hematology,Xiangtan Central Hospital,Xiangtan,Hunan 411100,P.R.China;[5]Department of Hematology,Hunan Provincial People’s Hospital,the First Affiliated Hospital of Hunan Normal University,Changsha,Hunan 410005,P.R.China;[6]Department of Hematology,Hunan Children’s Hospital,Changsha,Hunan 410005,P.R.China;[7]Hunan Key Laboratory of Tumor Models and Individualized Medicine,Changsha,Hunan 410011,P.R.China

出　　处：《Cancer Communications》索引2020年第40卷第10期,共17页

基　　金：This work was supported by the National Natural Science Foundation of China(81200368,81670160);the Hunan Natural Science Foundation(2017JJ2355). 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. 关键词：CRISPR/Cas9 gene-editing LDHA oxamate T-cell lymphoblastic leukemia transgenic zebrafish model

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

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