Mechanisms of Resistance to Decitabine in the Myelodysplastic SyndromeReport as inadecuate




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Purpose

The DNA methylation inhibitor 5-aza-2′-deoxycytidine DAC is approved for the treatment of myelodysplastic syndromes MDS, but resistance to DAC develops during treatment and mechanisms of resistance remain unknown. Therefore, we investigated mechanisms of primary and secondary resistance to DAC in MDS.

Patients and Methods

We performed Quantitative Real-Time PCR to examine expression of genes related to DAC metabolism prior to therapy in 32 responders and non-responders with MDS as well as 14 patients who achieved a complete remission and subsequently relapsed while on therapy secondary resistance. We then performed quantitative methylation analyses by bisulfite pyrosequencing of 10 genes as well as Methylated CpG Island Amplification Microarray MCAM analysis of global methylation in secondary resistance.

Results

Most genes showed no differences by response, but the CDA-DCK ratio was 3 fold higher in non-responders than responders P<.05, suggesting that this could be a mechanism of primary resistance. There were no significant differences at relapse in DAC metabolism genes, and no DCK mutations were detected. Global methylation measured by the LINE1 assay was lower at relapse than at diagnosis P<.05. On average, the methylation of 10 genes was lower at relapse 16.1% compared to diagnosis 18.1% P<.05.MCAM analysis showed decreased methylation of an average of 4.5% range 0.6%–9.7% of the genes at relapse. By contrast, new cytogenetic changes were found in 20% of patients.

Conclusion

Pharmacological mechanisms are involved in primary resistance to DAC, whereas hypomethylation does not prevent a relapse for patients with DAC treatment.



Author: Taichun Qin , Ryan Castoro , Samih El Ahdab , Jaroslav Jelinek, Xiaodan Wang, Jiali Si, Jingmin Shu, Rong He, Nianxiang Zhang, Wo

Source: http://plos.srce.hr/



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