Key Points• cAMP inhibits p53 accumulation and cell death in BCP-ALL cells but not normal BCPs, providing a possible therapeutic window for intervention.• Activation of the PGE 2 -cAMP-PKA axis might be exploited by leukemic cells to suppress oncogene-and treatmentinduced p53 activation.B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most commonly occurring pediatric cancer. Despite its relatively good prognosis, there is a steady search for strategies to improve treatment effects and prevent the undesired side effects on normal cells. In the present paper, we demonstrate a differential effect of cyclic adenosine monophosphate (cAMP) signaling between normal BCPs and BCP-ALL blasts, pointing to a potential therapeutic window allowing for manipulation of cAMP signaling in the treatment of BCP-ALL. By studying primary cells collected from pediatric BCP-ALL patients and healthy controls, we found that cAMP profoundly decreased basal and DNA damage-induced p53 levels and cell death in malignant cells, whereas normal BCP counterparts displayed slightly augmented cell death when exposed to cAMPincreasing agents. We did not find evidence for a selection process involving generation of increased basal cAMP levels in BCP-ALL cells, but we demonstrate that paracrine signaling involving prostaglandin E 2 -induced cAMP generation has the potential to suppress p53 activation and cell death induction. The selective inhibitory effect of cAMP signaling on DNA damage-induced cell death in BCP-ALL cells appears to be an acquired trait associated with malignant transformation, potentially allowing the use of inhibitors of this pathway for directed killing of the malignant blasts. (Blood. 2013;121(10):1805-1813