title: Selective inhibition of cell death in malignant vs normal B-cell precursors: implications for cAMP in development and treatment of BCP-ALL.
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 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.
authors.affiliation: Department of Biochemistry, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
authors.forename: Elin Hallan
authors.initials: EH
authors.lastname: Naderi
authors.forename: Hege Katrin
authors.initials: HK
authors.lastname: Ugland
authors.forename: Phoi-Phoi
authors.initials: PP
authors.lastname: Diep
authors.forename: Dag
authors.initials: D
authors.lastname: Josefsen
authors.forename: Ellen
authors.initials: E
authors.lastname: Ruud
authors.forename: Soheil
authors.initials: S
authors.lastname: Naderi
authors.forename: Heidi Kiil
authors.initials: HK
authors.lastname: Blomhoff
mesh_terms: D000293:Adolescent; D000328:Adult; D017209:Apoptosis; D001752:Blast Crisis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D016022:Case-Control Studies; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D004249:DNA Damage / Q000502:physiology / Q000528:radiation effects; D015232:Dinoprostone / Q000494:pharmacology; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D010120:Oxytocics / Q000494:pharmacology; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: D010120:Oxytocics; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D005576:Colforsin; D000242:Cyclic AMP; D015232:Dinoprostone