Project 1: Molecular determinants of decitabine responsiveness

Timothy Ley, MD, and John Welch, MD, PhD

The long-term goal of this project is to identify the patients with acute myeloid leukemia (AML) who are the most likely to respond to decitabine therapy, and to determine the molecular mechanisms of decitabine responses. TP53 mutated AML has the worst outcomes of all AML subgroups, with 1-year survival rates <20%. We recently reported that TP53 mutated AML and MDS patients respond consistently to decitabine, a hypomethylating agent that can be given as an outpatient. The molecular mechanisms associated with decitabine responses are currently unclear. To extend these findings, we will conduct a clinical trial focused on AML patients with TP53 mutations, and with disease that is relapsed or refractory after cytotoxic induction therapy. We also will explore the genomic and epigenomic signatures associated with decitabine responses, by performing whole-genome bisulfite sequencing (WGBS) and RNA-Seq on all patients (as shown below), to determine whether decitabine causes specific patterns of DNA hypomethylation, whether these changes result in consistent transcriptional signatures, and whether these patterns correlate with clinical outcomes.