The Bcr/Abl oncogene encodes a tyrosine kinase that is expressed in leukemias that carry the Philadelphia chromosome translocation (Ph+). The kinase interacts with different cell signaling pathways to cause factor-independent growth, resistance to apoptosis and oncogenic transformation. These pleiotropic activities of Bcr/Abl affect the pathogenesis of Ph+ leukemias by inhibiting the normal rate of cell death and by enabling Ph+ cells to resist conventional chemotherapy that induces apoptosis in other leukemias. A central hypothesis of this proposal is that inhibition of signaling pathways downstream of the Bcr/Abl kinase should render leukemia cells dependent on growth factors and sensitive to apoptosis. Perillyl alcohol (POH) belongs to a new family of chemotherapy agents and has shown excellent therapeutic rations in rodent carcinoma models. The range of potential anti-tumor activities of POH overlaps with some signaling pathways that are affected by the Bcr/Abl kinase. Thus, POH is a logical compound to test for anti- leukemia activity in Bcr/Abl-induced leukemia. Preliminary experiments demonstrated that in Bcr/Abl-transformed cells, POH rapidly induced G1 arrest and apoptosis. In contrast, Bcr/Abl- transformed cells were resistant to apoptosis induced by different conventional chemotherapy agents. This anti-leukemia activity of POH closely correlated with inhibition of the Raf-ERK signaling pathway downstream of Bcl/Abl. On the other hand, POH treatment did not affect other Bcr/Abl signals that are responsible for maintaining expression of c- Myc. Normally, expression of c-Myc is cell cycle regulated, however, when c-Myc expression is enforced during G1 arrest, cells undergo apoptosis. Therefore, POH may uncouple a Bcr/Abl signaling pathway through Raf that is necessary for maintaining cell growth, while not affecting other Bcr/Abl signals that induce constitutive c-Myc expression. This combination may lead to apoptosis in leukemia cells. This model will be evaluated further by examining 1) the role of the Bcr/Abl oncogene in sensitizing cells to POH, 2) how POH affects signaling through Raf, and 3) whether POH induces Myc-dependent apoptosis in leukemia cells.