Meeting abstracts from the 2024 UCD School of Medicine Summer Student Research Awards (SSRA 2024)

Acute Myeloid Leukaemia (AML) involves deviations from normal haematopoiesis due to genetic or epigenetic dysregulation.Polycomb Repressive Complex 2 (PRC2), an epigenetic modulator involved in histone trimethylation, is altered in 15% of AML cases, resulting in highly chemoresistant leukaemia with poor prognosis [1].AML cells also exhibit distinct metabolic profiles, including increased dependencies on specific amino acids (AAs).This study investigates the effect of PRC2 loss-of-function on AA metabolism in AML cell lines and aims to identify specific AA dependencies that could highlight novel therapeutic targets in EZH2-mutated AML.We subjected PRC2 haploinsufficient AML cell lines to AA depletion and analyzed them using trypan blue exclusion, alamar blue assays, cell cycle analysis via propidium iodide, and western blotting for apoptotic markers.Compared to wild-type cells, EZH2 loss-of-function cells maintained higher viability, particularly under cysteine depletion.In glutamine depletion, cell cycle analysis showed that most EZH2 lossof-function cells transitioned to and remained in the S phase.These results suggest that EZH2 haploinsufficient cells exhibit enhanced adaptability to specific AA depletions, leading to higher viability.The higher viability in AA depletion may be linked to S-phase progression and arrest, allowing for cell death avoidance.This can potentially translate to a selective advantage in vivo, where EZH2 haploinsufficient cells are more capable of surviving in stressful environments.Additionally, cell cycle S-phase arrest may present a potential targetable vulnerability for treatments affecting DNA replication.Further investigation into changes in AA metabolic pathways caused by EZH2 loss in AML cells is strongly encouraged.