Cyclic AMP-signaling in development and treatment of BCP-ALL
The focus of our research is to improve DNA damage-based treatment of BCP-ALL, with the goal to limit the severe side effects of the therapy. In order to identify new targets for improving the treatment of BCP-ALL, we study the role of cAMP-signaling in regulating DNA damage-induced apoptosis in the cells. We have shown that cAMP-signaling prevents DNA damage-induced p53 and cell death in BCP-ALL cells but not in normal B cell precursors, suggesting that cAMP-signaling might be a driving force in development of BCP-ALL. We have shown that bone marrow stromal cells provide BCP-ALLs with cAMP-activating signals like prostaglandine 2 (PGE2), and we have used inhibitors of PGE2 formation (indomethacin) to enhance DNA damage-induced killing of BCP-ALL. We have established a xenograft model of ALL in NSG mice, and we use In vivo imaging to show that indomethacin delays the progression of the leukemia in these mice. In our current projects, we study how cAMP signaling regulates the interplay between ROS, autophagy and survival of ALL cells in culture and in our animal model, and we are now also linking these events to metabolic changes in the cells.