Proposed model for MSC-derived PGE
-mediated cytoprotection of BCP-ALL. Mesenchymal stromal cells (MSC) produce prostaglandin E2 (PGE2) by the enzymatic conversion of arachidonic acid (AA) in a process depending on the action of cyclooxygenases (COX). PGE2 is then secreted into the extracellular space where it can signal in a paracrine manner by binding to the E prostanoid receptor 2 (EP2) on the surface of B cell precursor acute lymphoblastic leukaemia (BCP-ALL) cells. Binding of PGE2 to EP2 activates adenylate cyclase (AC) resulting in the enzymatic conversion of ATP to cAMP, which further activates target proteins such as protein kinase A (PKA). PKA activation attenuates p53 accumulation in BCP-ALL cells thereby inhibiting DNA damage-induced p53-dependent cell death. Non-steroidal anti-inflammatory drugs (NSAIDs) or PKA inhibitors can interfere with this cascade of events with the potential of reversing the MSC-mediated protection of BCP-ALL cells during DNA-damaging therapy.