Selective inhibition of cell death in malignant vs normal B-cell precursors: Implications for cAMP in development and treatment of BCP-ALL

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Abstract

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 E2-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. © 2013 by The American Society of Hematology.

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Naderi, E. H., Ugland, H. K., Diep, P. P., Josefsen, D., Ruud, E., Naderi, S., & Blomhoff, H. K. (2013). Selective inhibition of cell death in malignant vs normal B-cell precursors: Implications for cAMP in development and treatment of BCP-ALL. Blood, 121(10), 1805–1813. https://doi.org/10.1182/blood-2012-08-452698

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