<scp>BSH</scp> 2023 e‐Poster abstract book
Antioxidant signalling has been shown to play a significant role in both the leukaemic stem cells (LSCs) and haematopoietic stem cells (HSCs). In a hypoxic environment these bone-marrow resident cells are characterised by their increased quiescence. This decreasing in cell division causes a problem for the HSCs, as most cells deal with oxidative damage (to both proteins and DNA) throughout cell divisions. Therefore, these cells require different strategies to manage oxidative damage. Prostaglandins enhance protection mechanisms against oxidative stress by reducing reactive oxygen species (ROS). Prostaglandin G/H synthases (PTGS1/2) are the key catalysts in prostaglandin synthesis. It has been shown the product of PTGS1/2 activity PGE2, supports HSC survival, proliferation and homing in the niche. Here we present data that supports a role for analogous PTGS1/2 signalling being protective in AML.
Abstract
Background: Antioxidant signalling has been shown to play a significant role in both the leukaemic stem cells (LSCs) and haematopoietic stem cells (HSCs).In a hypoxic environment these bone-marrow resident cells are characterised by their increased quiescence.This decreasing in cell division causes a problem for the HSCs, as most cells deal with oxidative damage (to both proteins and DNA) throughout cell divisions.Therefore, these cells require different strategies to manage oxidative damage.Prostaglandins enhance protection mechanisms against oxidative stress by reducing reactive oxygen species (ROS).Prostaglandin G/H synthases (PTGS1/2) are the key catalysts in prostaglandin synthesis.It has been shown the product of PTGS1/2 activity PGE2, supports HSC survival, proliferation and homing in the niche.Here we present data that supports a role for analogous PTGS1/2 signalling being protective in AML.Methods: The role of PTGS genes in AML outcome was studied through a combination of bioinformatics, biochemistry and cellular and molecular biology techniques.Bioinformatics databases were analysed to evaluate PTGS1/2 expression in AML and how this affects overall survival and patient outcomes.We also assessed the efficacy of PTGS1 inhibitors (SC560, Tenidap) in AML cell lines.We used flow cytometry to assess apoptosis and cell cycle.Lentiviral overexpression of PTGS1 and PTGS2 was carried out in U937 and HL-60 to determine the contribution of these genes to survival, proliferation and drug resistance.Lastly, we examined the role of PTGS1/2 in promoting immunosuppression in AML.Results: Bioinformatic analysis of publicly available databases showed elevated expression of PTGS1 but not PTGS2 is associated with HSCs, decreasing with lineage commitment in myeloid progenitors.Significantly, elevated PTGS1 expression is associated with decreased overall survival in AML datasets (TCGA, Verhaak) but no association is seen with PTGS2.In vitro data demonstrate that PTGS1 inhibition (SC560,