Cell Death Pathways: Sensitivity and Resistance in Leukemia

Research on cell death programs has now entered a phase of translation into clinical application. Cancer is a complex disease. Research in our own laboratory has aimed to identify mechanisms of apoptosis resistance in tumor cells and identified e.g. proteins of the IAP-family as key modulators and inhibitors of cell death induction by death receptor agents such as TRAIL and cytotoxic drugs. Translation of apoptosis research into clinical application has to deal with the complexity and heterogeneity of clinical tumor. In a NOD/SCID mouse model for pediatric acute lymphoblastic leukemia we have addressed issues of apoptosis sensitivity and resistance of primary individual leukemia cells of patients as well as issues related to identification of leukemia initiating cells or leukemia stem cells in such populations. We have identified deficient cytochrome C-related caspase activation in individual leukemia cells as highly important prognostic marker for ALL and AML, established specific gene signatures for poor prognosis ALL, associated with rapid engraftment in the mouse model and found that rapid engraftment in the mouse and poor prognosis in the patient is directly correlated to a functionally apoptosis-deficient phenotype. We have also addressed issues of coordinated inhibition of tyrosine kinase signaling, inhibition of the mTOR pathway and apoptosis induction by cytotoxic drugs and/or apoptosis-inducing ligands and exploited such strategies for treatment of patients with end-stage and advanced tumors. The identification of functional molecular signatures into rational treatment strategies will be the challenge for translating basic mechanisms of the cell death machinery into clinically relevant application for diagnosis and treatment of tumors.