Childhood acute lymphoblastic leukemia is a disease with a good prognosis nowadays. However, there are still patients suffering from relapse or toxic side effects of conventional therapy. This is why there is a need to improve the therapy further and reduce side effects. Smac Mimetics (SM), mimicking the pro apoptotic function of the endogenous protein SMAC have been shown to induce cell death in various cancer entities as a single agent or in combinational therapy regimes. A detailed characterization of SM’s mode of action in pediatric ALL is the main objective of this thesis. This aim will be achieved by identifying BCP-/T-ALL cell lines with sensitivity to SM-induced cell death to compare them with SM-insensitive ones. The efficacy of SM-induced cell death between monovalent and bivalent SMs will be compared. To characterize the mode of cell death induced by the different SMs, different cell death assays with blockage of key regulators of apoptosis and necroptosis will be performed. Western blots will be done to follow up the apoptotic cell signaling and caspase activation. The role of TNF-alpha in SM-induced cell death will be investigated by adding TNF-alpha blocking antibodies. These findings may lead to the identification of a predictor of SM-sensitivity. Furthermore, potential non-killing effects of SM on BCP-/T-ALL cells will be investigated. Last but not least a group of primary patient-derived xenograft cells will be examined regarding their (in)sensitivity to SM-induced cell death.
