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

Cancer Communications 2020年第10期40卷 501-517页

作者： Haizhi Yu Yafei Yin Yifang Yi Zhao Cheng Wenyong Kuang Ruijuan Li Haiying Zhong Yajuan Cui Lingli Yuan Fanjie Gong Zhihua Wang Heng Li Hongling Peng Guangsen Zhang Department of Hematology the Second Xiangya HospitalCentral South UniversityChangshaHunan 410011P.R.China Institute of Hematology Central South UniversityChangshaHunan 410011P.R.China Department of Respiratory and Critical Medicine NHC Key Laboratory of Pulmonary Immune-related DiseasesPeople’s Hospital of Guizhou UniversityGuizhou Provincial People’s HospitalGuiyangGuizhou 550002P.R.China Department of Hematology Xiangtan Central HospitalXiangtanHunan 411100P.R.China Department of Hematology Hunan Provincial People’s Hospitalthe First Affiliated Hospital of Hunan Normal UniversityChangshaHunan 410005P.R.China Department of Hematology Hunan Children’s HospitalChangshaHunan 410005P.R.China Hunan Key Laboratory of Tumor models and Individualized Medicine ChangshaHunan 410011P.R.China

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 *** proposed that targeting LDHA may be a potential strategy to improve T-ALL *** current study was conducted to investigate the antileukemic effect of LDHA gene-targeting treatment on T-ALL and the underlying molecular ***:Primary T-ALL cell lines Jurkat and DU528 were treated with the LDH inhibitor ***,colony formation,apoptosis,and cell cycle assays were performed to investigate the effects of oxamate on T-ALL *** 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 ***:Oxamate significantly inhibited proliferation and induced apoptosis of Jurkat and DU528 *** also arrested Jurkat and DU528 cells in G0/G1 phase and stimulated ROS production(all Ptransgenic ***: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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