Hypermethylation Of Cpg Sites At The Promoter Region Is Associated With Deregulation Of Mitochondrial Atpsyn-Beta And Chemoresistance In Acute Myeloid Leukemia

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 beta subunit of mitochondrial ATP synthase (ATPsyn-beta) leads to adriamycin resistance in acute and chronic myeloid leukemia cells, and hypermethylation of the ATPsyn-beta gene promoter is associated with chemoresistance in chronic myeloid leukemia.OBJECTIVE: To further investigate the relationship between methylation of ATPsyn-beta 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-beta 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-beta 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-beta mRNA expression and increase the adriamycin sensitivity of primary leukemic cells from seven relapsed/refractory AML patients.CONCLUSIONS: Hypermethylation of ATPsyn-beta gene promoter is associated with a down-regulated mRNA expression and chemoresistance in AML patients.