- Main
Mechanisms of DNA hypomethylating agents in acute myeloid leukemia
- Dai, Raymond
- Advisor(s): Costello, Joseph
Abstract
Aberrant DNA methylation is a hallmark of many cancers. As such, there has been substantial interest in the development of anti-cancer strategies which modulate epigenetic programs associated with alterations in DNA methylation. In acute myeloid leukemia (AML), decitabine is a clinically-approved DNA hypomethylating agent used for a subset of high-risk patients with poor prognoses. Despite the clinical use of this drug, and clear evidence of a clinical benefit for this patient cohort, the mechanisms by which decitabine acts as an anti-cancer agent through perturbing DNA methylation remains poorly understood. In this research, we describe our approach using functional genomics and multiomics to examine the mechanisms by which decitabine acts to kill cancer cells in the context of AML. More specifically, our results unexpectedly reveal RNA dynamics as key regulators of DNA hypomethylation induced cell death in AML. Specifically, we show that RNA decapping quality control promotes cellular resistance to DNA hypomethylation, and conversely, we also observe that RNA methylation promotes cellular sensitivity to DNA hypomethylation. Overall, our findings linking RNA dynamics to DNA methylation suggests new levels of cellular integration between RNA and DNA regulatory biology that may aid in the design of future therapeutic strategies.
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