A multiomics approach reveals RNA dynamics promote cellular sensitivity to DNA hypomethylation

The search for new approaches in cancer therapy requires a mechanistic understanding of cancer vulnerabilities and anti-cancer drug mechanisms of action. Problematically, some effective therapeutics target cancer vulnerabilities that have poorly defined mechanisms of anti-cancer activity. One such drug is decitabine, a frontline therapeutic approved for the treatment of high-risk acute myeloid leukemia (AML). Decitabine is thought to kill cancer cells selectively via inhibition of DNA methyltransferase enzymes, but the genes and mechanisms involved remain unclear. Here, we apply an integrated multiomics and CRISPR functional genomics approach to identify genes and processes associated with response to decitabine in AML cells. Our integrated multiomics approach reveals RNA dynamics are key regulators of DNA hypomethylation induced cell death. Specifically, regulation of RNA decapping, splicing and RNA methylation emerge as critical regulators of cellular response to decitabine. ### Competing Interest Statement A.Y.G., A.A. and R.D. declare no competing interests. K.K., M.B.P. and M.T.M. are employees and shareholders of GSK. L.A.G. has filed patents on CRISPR functional genomics and is a co-founder of Chroma Medicine. The data that support the findings of this study are openly available in NCBI Gene Expression Omnibus (GEO) with reference number GSE222886 (RNA-seq, meRIP-seq, Ribo-seq).