Transcriptional Addiction in Acute Myeloid Leukemia
Project Goal: Validate and mechanistically characterize MEF2D and IRF8 as potential therapeutic targets in pediatric AML
Institution: Dana Farber Cancer Institute, Boston Children’s Hospital, Harvard Medical School
Researchers: Max Pimkin, MD, PhD
Year Awarded: 2019
Type of Childhood Cancer: MLL-Rearranged Acute Myeloid Leukemia (AML)
MLL-rearranged acute myeloid leukemia (AML) is a subtype of pediatric AML with extremely poor prognosis. In our prior study, we identified the transcription factors MEF2D and IRF8 as strong selective dependencies in MLL-rearranged AML. Importantly, our preliminary data indicates that inhibition of MEF2D does not impair normal blood development. This suggests a potential “Achilles heel” for leukemia-specific therapy with little or no detrimental effects on normal tissues. We propose to investigate the mechanism of transcriptional addiction of MLL-rearranged AML to MEF2D and IRF8 using a combination of genetic, biochemical and systems biology approaches. In addition, we propose to use an engineered chemical degradation system to evaluate the therapeutic potential of MEF2D and IR8 inhibition in a mouse model of human AML. Our study will validate and mechanistically characterize MEF2D and IRF8 as potential therapeutic targets in pediatric AML.