ABSTRACT The long-term goal of this project is to elucidate the role, regulation and therapeutic relevance of sphingomyelin synthase (SMS) in cancer. The current proposal focuses on Chronic Myelogenous Leukemia (CML) but our observations suggest that SMS may be relevant in other neoplasms, such as breast cancer. SMS contributes to lipid metabolism by synthesizing the sphingolipid sphingomyelin (SM). Importantly, in the course of its reaction, SMS consumes ceramide and produces diacylglycerol (DAG), two critical bioactive lipids with opposing functions in the control of key cellular processes that include proliferation, apoptosis, and differentiation. Because of the regulation of ceramide and DAG, SMS is poised to be linked to cancer, but current knowledge about this potential link is very limited. In mammals, there are two SMS enzymes (SMS1 and SMS2) encoded by two distinct genes (SMS1 and SMS2). At this time, nothing is known about SMS1 or SMS2 upstream regulation and their potential downstream signaling functions in cancer biology. Preliminary data from the PI's laboratory establish a novel connection between SMS1 and the BCR- ABL oncogene, responsible for the onset of CML. Importantly, preliminary results from the PI's laboratory support the hypothesis that BCR-ABL1 enhances expression of SMS1 through a novel concerted mechanism of transcriptional/translational regulation and that elevated SMS1 activity sustains the tumorigenic potential of CML cells. To test this hypothesis we will: 1. Determine the role of SMS1 in CML pathobiology and its mechanism of action and 2. Elucidate the mechanism of SMS1 regulation by BCR- ABL1. The discovery of the BCR-ABL1/SMS1 connection provides the first molecularly defined model for a better understanding of potential modes of regulation and down-stream functions of the elusive SMS1 in a cancer model and establishes novel connections in the bcr-abl signaling network potentially uncovering novel pharmacological targets for CML. Moreover the identification of the direct upstream regulators of SMS1 might uncover the association of SMS1 with other pathologies (including other types of cancers) in which the newly characterized upstream regulator is a critical determinant.

PROJECT NARRATIVE Our goal is to establish the lipid-metabolizing enzyme, Sphingomyelin Synthase 1 (SMS1) as a novel important down-stream target of the BCR-ABL1 oncogene and to establish SMS1's role in the development of Chronic Myelogenous Leukemia.