Oncotarget

Research Papers:

Novel impact of the DNMT3A R882H mutation on GSH metabolism in a K562 cell model established by TALENs

Li Yang, Ya'Nan Liu, Na Zhang, Xiao'Yi Ding, Wei Zhang, Ke'Feng Shen, Liang Huang, Jian'Feng Zhou, Sen Cui, Zun'Min Zhu, Zheng Hu and Min Xiao _

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Oncotarget. 2017; 8:30395-30409. https://doi.org/10.18632/oncotarget.16449

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Abstract

Li Yang1,*, Ya’Nan Liu2,*, Na Zhang3, Xiao’Yi Ding1, Wei Zhang1, Ke’Feng Shen1, Liang Huang1, Jian’Feng Zhou1,6, Sen Cui7, Zun’Min Zhu8, Zheng Hu4,5, Min Xiao1

1Department of Hematology, Tongji Hospital Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, P.R.China

2Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei Province, P.R. China

3Department of Hematology, Xijing Hospital Affiliated by The Fourth Military Medical University (FMMU), Xi'an, Shanxi Province, P.R.China

4Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

5Department of Obstetrics and Gynecology, The First Affiliated Hospital, Sun Yat-Sen 14 University, Guangzhou, Guangdong, China

6Qinghai University, XiNing, Qinghai Province, P.R.China

7Department of Hematology, Qinghai University Affiliated Hospital, Qinghai University, XiNing, Qinghai Province, P.R.China

8Department of Hematology, Henan Provincial People’s Hospital, ZhengZhou, Henan Province, P.R.China

*These authors have contributed equally to this work

Correspondence to:

Min Xiao, email: Xiaomin@tjh.tjmu.edu.cn

Zheng Hu, email: Huzheng1998@163.com

Keywords: DNMT3A R882H mutation, TALENs, K562, GSH, SLC7A11

Received: January 02, 2016     Accepted: February 20, 2017     Published: March 22, 2017

ABSTRACT

DNA methyltransferase 3A (DNMT3A) mutations occurred in 18%~23% of acute myeloid leukemia (AML) patients, and were considered to be an adverse prognostic factor for adult de novo AML cases. However, the relevant molecular mechanism of the mutation in AML pathogenesis remains obscure. In this study, we established K562 and SKM1 cell model carrying the DNMT3A R882H mutation via transcription activator-like effector nuclease (TALEN) and Clustered regularly interspaced short palindromic repeats (CRISPR/Cas9) technology, and discovered that mutated DNMT3A could promote the proliferative capability of malignant cell clones. Further RNA microarray analysis revealed that some genes crucial for glutathione (GSH) synthesis, including CTH, PSPH, PSAT1 and especially SLC7A11 (the cysteine/glutamate transporter) were significantly up-regulated, which resulted in significant elevation of intracellular GSH levels. A subsequent experiment demonstrated that the mutant clones are resistant to chemotherapy as well as SLC7A11-inhibitorsBy shRNA induced SLC7A11 silencing, we discovered profoundly decreased cellular GSH and cell proliferative ability of DNMT3A mutated clones. Our results provided novel insight into the role of the DNMT3A R882H mutation in AML pathogenesis and suggested that targeting the cellular GSH synthetic pathway could enhance the current therapy for AML patients with the DNMT3A R882H mutation.


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