Tumor necrosis factor α knockout impaired tumorigenesis in chronic myeloid leukemia cells partly by metabolism modification and miRNA regulation

• Main Authors: Shen N, Liu S, Cui J, Li Q, You Y, Zhong Z, Cheng F, Guo AY, Zou P, Yuan G, Zhu X
• Format: Article
• Language: English
• Published: Dove Medical Press 2019-03-01
• Series: OncoTargets and Therapy
• Subjects: Chronic myeloid leukemia; Tumor necrosis factor α; CRISPR/Cas9 gene editing; Tumorigenesis; Metabolism profile.
• Online Access: https://www.dovepress.com/tumor-necrosis-factor-alpha-knockout-impaired-tumorigenesis-in-chronic-peer-reviewed-article-OTT

Na Shen,1,* Songya Liu,2,* Jieke Cui,3 Qing Li,4 Yong You,1 Zhaodong Zhong,1 Fanjun Cheng,1 An-Yuan Guo,5 Ping Zou,1 Guolin Yuan,6 Xiaojian Zhu2 1Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; 2Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; 3Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; 4Department of Hematology, Wuhan No 1 Hospital, Wuhan 430022, China; 5Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China; 6Department of Hematology, Xiangyang Central Hospital, The Affiliated Hospital of Hubei University of Arts and Science, Xiangyang 441000, China *These authors contributed equally to this work Purpose: Half of the chronic myeloid leukemia (CML) patients with sustained deep molecular response suffer from relapse after discontinuation mainly because tyrosine kinase inhibitors (TKIs) cannot eradicate leukemia stem cells (LSCs). In addition, tumor necrosis factor α (TNF-α) is highly detected in CML patients. Our aim was to explore whether TNF-α is a potential target for LSC elimination.Materials and methods: We applied a CRISPR/Cas9 gene editing technique, colony-forming cell assay, subcutaneous tumor models, miRNA-seq and liquid chromatography-mass spectroscopy (LC-MS) on metabonomics to explore the feasibility and mechanism of TNF-α as a new therapeutic target for CML.Results: We demonstrated that TNF-α knockout remarkably decreased the proliferative, colony-forming and in vivo tumorigenesis capacities of the CML K562 cell line. The apoptosis was increased when TNF-α knockout cells were cultured with imatinib. The mechanisms involved in the abovementioned phenomena were that TNF-α knockout inhibited the citrate cycle and increased starch, sucrose, amino sugar and nucleotide sugar metabolism. In addition, differentially expressed miRNAs between TNF-α knockout and control cells were involved in the cell cycle, CML, P13K-Akt and pathways in cancer.Conclusion: We identified that TNF-α may serve as a new target therapy for CML and described the metabolic pathways associated with TNF-α in CML cells for the first time. Keywords: chronic myeloid leukemia, tumor necrosis factor α, CRISPR/Cas9 gene editing, tumorigenesis, metabolism profile