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OBJECTIVE: Chronic myeloid leukemia (CML) is a hematological disease which is known by the presence of Philadelphia chromosome (Ph+). BCR-ABL protein is expressed by Ph+ chromosome, represents constant increased tyrosine kinase activity. Imatinib (IMA) is a tyrosine kinase inhibitor (TKI) which is utilized as a first line treatment in CML. Emergence of IMA resistance at some point of therapy leads to treatment failure. DNA methylation is considered to be the most stable epigenetic change and several studies have shown that epigenetic changes may play a role in drug resistance. We investigated the global methylation profile of IMA-sensitive K562S, IMA-resistant K562R and IMA-resistant and adherent K562R (K562R-adh) cells to determine whether epigenetic reprogramming is involved in the resistance to IMA and the change in phenotype due to this resistance. MATERIAL AND METHODS: In this study, morphologically distinct, IMA-sensitive K562S and 5µM IMA-resistant K562R and K562R-adh in-vitro CML cell models were used to analyze the global DNA methylation profile. After DNA was isolated from the cells, global 5mC DNA methylation profiles were investigated by ELISA using equal amounts of DNA. RESULTS: Compared to K562S, the global methylation of K562R showed an increase in DNA methylation profile, but this increase in methylation was not statistically significant. Whereas, a slight hypermethylation was observed in the DNA of the K562R-adh vs K562S and K562R-adh vs K562R which is statistically significant. We observed slight hypermethylation in IMA-resistant cells lines versus to the IMA-sensitive cell line. CONCLUSION: Our observed differences in 5methyl-Cytosine on CpG islands (5mC) in K562S versus K562R and K562R-adh cell lines suggest that the DNA methylation alteration in resistant cells may partly contributed in phenotype switching.
Yalda Hekmatshoar (Mon,) studied this question.