The successful eradication of leukemic cells depends on induction of apoptosis. Defects in apoptosis pathways, therefore, can contribute to chemoresistance and treatment failures. Apoptosis results from the activation of a family of intracellular proteinases, known as caspases. The proteases are functionally connected to each other through cascades of proteolysis whereby upstream (initiator) caspases cleave and activate downstream (effector) caspases. At present, three major pathways for initiation of caspase activation have been revealed: (a) mitochondria/cytochrome c, which activates pro-caspase-9; (b) TNF- family death receptors, which activate pro-caspases. The goals of this proposal are to functionally map the status of these 3 pathways in AML cells, thereby determining whether roadblocks to apoptosis reside in specific caspase activation pathways. The heterogeneity of apoptosis roadblocks will be elucidated through comparisons of patient specimens representing early-stage, responsive disease versus late-stage, treatment- refractory disease. Attempts to the specific pathways utilized by cytotoxic anti-cancer drugs for inducing apoptosis in AMLs will be elucidated. Recognizing that core components of the apoptosis machinery of cells are regulated by signal transduction pathways, another goal of the proposal is to determine the effects on apoptosis pathways of kinase inhibitors, retinoids, and other agents that affect signal transduction pathways and transcriptional programs., in search of strategies for effectively sensitizing AML cells to apoptotic stimuli provided by anti-cancer drugs, the immune system, or both. Finally, a functional genomics strategy will be employed in search of novel anti-apoptotic proteins from treatment refractory AMLs, which may serve as future targets fro drug discovery.