Highly-Sensitive DNA Hydroxymethylation Analysis in Myelodysplastic Syndromes (MDS)

Abstract

Aberrant DNA hydroxymethylcytosine (5hmC) levels have been reported in patients with myelodysplastic syndromes (MDS). The dysregulation of 5hmC is not only observed in patients with TET2 mutations, but also those bearing other genetic defects, suggesting that 5hmC might act as a valuable epigenetic mark to reflect the status of MDS. We report herein a highly-sensitive 5hmC analysis method using low input DNA (10 ng), which was used to obtain a comprehensive atlas of the DNA hydroxymethylome in MDS patients. Our systematic bioinformatic analysis unveiled that 5hmC signatures could be used to separate patients with good and poor clinical outcomes. At the molecular level, we observed dynamic changes of 5hmC within several key transcription factor binding motifs that are essential for hematopoiesis and myeloid lineage specification, which might result in impaired transcriptional outputs during leukemogenesis. Interestingly, we also observed massive changes in 5hmC and transcriptomes in patient showing response to hypomethylating agent (HMA) treatment, suggesting the prognostic value of 5hmC in evaluating epigenetic therapy. Overall, our highly-sensitive 5hmC analysis method provides a useful means to potentially facilitate the clinical evaluation of MDS patients. Disclosures Garcia-Manero: AbbVie: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Onconova: Research Funding; Amphivena Therapeutics: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Jazz Pharmaceuticals: Consultancy; Acceleron Pharmaceuticals: Consultancy, Honoraria; H3 Biomedicine: Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding.