Whole Genome MBD-seq reveals different CpG methylation patterns in Azacytidine-treated JMML patients. Genome-wide study of CpG DNA methylation of individuals affected by pediatric myelodisplasia before and after pharmacological treatment

Juvenile Myelomonocytic Leukemia (JMML) is a rare and aggressive leukemia of early childhood. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only available curative treatment, but more than 30% of patients experience leukemia relapse; thus, developing alternative therapeutic approaches is desirable. Aberrant DNA methylation at specific genetic loci is a key molecular feature of JMML, suggesting an important role of epigenetic events in the pathophysiology of the disease. Azacytidine (AZA), a molecule that inhibits DNA methylation in human cells, is under investigation in patients with JMML. Here, we report a global evaluation of DNA methylation status of CD34+ cells obtained from JMML patients before and after AZA treatment and compared the results with those of healthy controls. Through a MBD-Seq technology, we identified global DNA hypermethylation in both pre- and post- AZA-treated patient and a significant, although patient-specific, AZA-induced hypomethylating effect. This signature includes coding and non-coding elements, depicting epigenetic dysregulation, which could have manifold consequences on transcriptional and translational processes. Last, we also found several retrotransposable elements showing DNA hypermethylation; considering their known ability of inducing genomic instability and transcription of adjacent genes in both sense and antisense directions, a possible role for these elements could emerge from further studies.