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Abstract Treatment decision and response assessment in myelodysplastic syndromes (MDS) can be enhanced by the implementation of advanced diagnostic and prognostic assays for the detection of multiple molecular features. Higher-risk (HR) MDS, ineligible for allogeneic hematopoietic stem cell transplantation (alloHSCT), require prompt therapeutic interventions such as treatment with hypomethylating agents (HMAs) to restore normal DNA methylation levels, mainly of oncosuppressor genes and consequently to delay disease progression and increase overall survival (OS). However, response assessment to HMA treatment relies on conventional methods with limited capacity to uncover a wide spectrum of molecular events. We studied bone marrow aspirates from twenty-one HR MDS patients pre- and post-HMA treatment and seven healthy controls. Genomic DNA was analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) for 5’ methyl-cytosine (5mC), 5’ hydroxy-methyl cytosine (5hmC) levels detection, and global adenosine/thymidine (dA/T) ratio, to correlate differences during treatment course and at baseline state prior drug therapy. Results from methylation DNA sequencing (MeD-seq) from the same HR MDS cohort were also analyzed to identify targeted differentially methylated regions (DMRs). LC/MS-MS analysis revealed a significant hypomethylation status in responders (Rs) already established at baseline and a trend for further DNA methylation reduction post-HMA treatment. Non-responders (NRs) reached statistical significance for DNA hypomethylation only post-HMA treatment. MeD-seq confirmed results globally for both Rs and NRs and more specifically, identified DMRs associated with HMA treatment. Additionally, within statistically significant selected chromosomal bins, genes encoding for proteins and non-coding RNAs were highlighted with reversed methylation profiles between Rs and NRs. Dynamic DNA methylation changes in HR MDS patients undergoing HMA therapy demonstrated that response to treatment is associated only with few specific hypomethylated DMRs rather than presenting a global effect across genome. The 5hmC epigenetic mark was only rarely detected in Rs and NRs, in contrast to healthy controls. Global dA/T ratio was lower in both R and NR subgroups compared to controls suggesting high frequences of baseline transitions from 5mC to thymidine. Conclusively, LC-MS/MS methodology provided broad-based but rapid and cost-effective results on the molecular HR MDS background, potentially translatable into responsive phenotypes to HMA treatment.
Nikolopoulos et al. (Thu,) studied this question.