Polycomb inhibition sensitizes AML to anthracycline therapy

The Research Institute at Nationwide Children’s Hospital, Columbus, OH

Childhood acute myeloid leukemia (AML) is an aggressive blood cancer driven from undifferentiated populations of myeloid cells that inappropriately proliferate and fail to differentiate. The major genetic drivers of childhood AML include mutations to epigenetic machinery, which functions to organize the DNA inside of the cell. Undifferentiated tumors, including subtypes of childhood AML with stem-like characteristics, are associated with high expression levels of Polycomb genes, encoding proteins which can epigenetically silence regions of DNA. This proposal builds on my hypothesis that drugs targeting Polycomb/EZH2 can help lower the dose of co-administered anthracyclines which are a toxic therapy for childhood AML. My preliminary data indicates that across cell models for several AML subtypes, inhibiting EZH2 enables lowering the effective dose of anthracycline by more than 5-fold. This proposed study aims to understand why we are observing this effect, to connect basic questions about the organization of DNA inside the leukemia cells to translational studies with patient-derived samples at Nationwide Children’s Hospital. This proposal will build on a collaboration with AML clinicians and physican-scientists, including Dr. Terri Guinipero, Dr. Huifei Liu and Dr. Ryan Roberts. We will define how DNA accessibility affects the function of anthracyclines in childhood AML.