Hypermethylation of CpG sites at the promoter region is associated with deregulation of mitochondrial ATPsyn-β and chemoresistance in acute myeloid leukemia

Article type: Research Article

Authors: Yang, Jingke^{a; b} | Xiao, Xiang^a | Li, Ruijuan^a | Li, Zijian^a | Deng, Mingyang^a | Zhang, Guangsen^{a; *}

Affiliations: [a] Division of Hematology, Institution of Molecular Hematology, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, China | [b] Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, China

Correspondence: [*] Corresponding author: Guangsen Zhang, Division of Hematology, Institute of Molecular Hematology, Second Xiang-Ya Hospital, Central South University, Changsha, Hunan 410011, China. E-mail:zgsllzy@163.com

Abstract: BACKGROUND: Aberrant DNA methylation status of some genes has been shown to be involved in chemoresistance of acute myeloid leukemia (AML). We have recently found that down-regulation of the β subunit of mitochondrial ATP synthase (ATPsyn-β) leads to adriamycin resistance in acute and chronic myeloid leukemia cells, and hypermethylation of the ATPsyn-β gene promoter is associated with chemoresistance in chronic myeloid leukemia. OBJECTIVE: To further investigate the relationship between methylation of ATPsyn-β gene, mRNA expression as well as chemoresistance in AML. METHODS: Quantitative RT-PCR and methylation specific PCR were performed to assess mRNA expression and methylation status of ATPsyn-β gene on primary bone marrow nuclear cells (BMMCs), and cell proliferation assay was used to determine the sensitivity of BMMCs to adriamycin. RESULTS: Hypermethylation status of ATPsyn-β gene promoter existed in those relapsed/refractory AML patients, and this hypermethylation of the gene was associated with a suppressed mRNA expression levels. Four patients at diagnosis and relapse underwent gene methylation status shift from hypermethylation to hypomethylation, which was accompanied by reduced mRNA expression of the gene. 5-azacitidine(5-Aza)- a demethylating agent, could restore ATPsyn-β mRNA expression and increase the adriamycin sensitivity of primary leukemic cells from seven relapsed/ refractory AML patients. CONCLUSIONS: Hypermethylation of ATPsyn-β gene promoter is associated with a down-regulated mRNA expression and chemoresistance in AML patients.

Keywords: Methylation, mitochondrial ATP synthase, chemoresistance, acute myeloid leukemia

DOI: 10.3233/CBM-150543

Journal: Cancer Biomarkers, vol. 16, no. 1, pp. 81-88, 2016