Molecular Profiling of Decitabine Response in MDS and AML Patients

The underlying molecular effects of decitabine treatment in MDS and AML patients are poorly understood. To systematically uncover the global genomic and transcriptomic alterations induced by decitabine in vivo, we evaluated a series of primary bone marrowf samples from patients treated with decitabine 20 mg/m2 on days 1-10 in 28 day cycles (NCT01687400). Samples were evaluated with: bulk-RNA sequencing (Day 0 & 10, n=29), single-cell RNA sequencing (Day 0 & 10, n=4), whole-genome bisulfite sequencing (WGBS, Day 0, 10, & 28, n=29), and exome sequencing (Day 0 & 28 n=44). Cases were selected for RNA-Seq and WGBS based on adequate sample availability, and founding clone mutations that were present in at least 75% of the cells in each sample on day 0. As expected, interpatient heterogeneity dominated global transcriptional variance across the bulk-RNA sequencing dataset, due to the unique mutational and cellular heterogeneity of each sample. We identified 638 significantly differentially expressed genes (DEGs) between day 0 and day 10. MSigDB-geneset analysis identified significant pathway enrichment of the day 10 upregulated genesets for myeloid maturation, immune activation, and cell cycle regulation, while down-regulated genesets were enriched for erythroid pathways, oxidative phosphorylation, cellular senescence, and metabolic processes (FDR In summary, this study provides insights into in vivo mechanisms of decitabine activity in AML and MDS patients, which includes global hypomethylation, myeloid maturation, induction of an inflammatory response, activation of specific ERV families, and strong interpatient heterogeneity. However, no specific transcriptional or epigenetic biomarkers emerged that could serve as effective predictors of decitabine responses. Disclosures Welch: ArcherDx: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Notable labs: Research Funding; Janssen research: Research Funding.