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

• Published in: Blood 2013-03, Vol.121 (10), p.1805-1813
• Main Authors: Naderi, Elin Hallan, Ugland, Hege Katrin, Diep, Phoi-Phoi, Josefsen, Dag, Ruud, Ellen, Naderi, Soheil, Blomhoff, Heidi Kiil
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Apoptosis; Blast Crisis - drug therapy; Blast Crisis - metabolism; Blast Crisis - pathology; Case-Control Studies; Cells, Cultured; Child; Child, Preschool; Colforsin - pharmacology; Cyclic AMP - metabolism; Dinoprostone - pharmacology; DNA Damage - physiology; DNA Damage - radiation effects; Female; Humans; Infant; Male; Oxytocics - pharmacology; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - pathology; Precursor Cells, B-Lymphoid - cytology; Precursor Cells, B-Lymphoid - metabolism; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Young Adult
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2012-08-452698

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 cAMP-increasing 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. •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 PGE2-cAMP-PKA axis might be exploited by leukemic cells to suppress oncogene- and treatment-induced p53 activation.