Epigenome-Based Drug Repositioning in Acute Myeloid Leukemia

Abstract

ABSTRACTBackgroundRepositioning approved drugs for the treatment of new indications is a promising avenue to reduce the burden of drug development. Most currently available computational methods based on molecular evidence can only utilize gene expression for repositioning despite a growing interest in the epigenome in human disease. We recently described a novel repositioning method, ksRepo, that enables investigators to move beyond microarray-based gene expression and utilize a variety of other sources of molecular evidence, such as DNA methylation differences.MethodsWe downloaded differential DNA methylation data from two publicly available acute myeloid leukemia (AML) datasets, a cancer with known, extensive epigenomic perturbations. We consolidated CpGs-level to non-directional gene-level differential methylation using Brown’s correction to Fisher’s method. We then used ksRepo, which ignores directionality in disease- and gene-drug associations, to mine the resulting prioritized gene lists and and the Comparative Toxicogenomics Database (CTD) for predicted repositioning candidates.ResultsWe successfully recovered four compounds that were significant (FDR < 0.05) in two AML datasets: cytarabine, alitretinoin, panobinostat, and progesterone. Cytarabine is the most commonly used frontline therapy for AML and alitretinoin, panobinostat, and progesterone have all been investigated for the treatment of AML.Conclusions. Combining a method for consolidating CpG methylation to the gene level with ksRepo provides a pipeline for deriving drug repositioning hypotheses from differential DNA methylation. We claim that our platform can be extended to other diseases with epigenetic perturbations and to other epigenomic modalities, such as ChIP-seq.