Treatment of childhood myelodysplastic syndromes (MDS) as well as chronic and acute myeloid leukemia (CML and AML) remains disappointing compared with well known advances in the treatment of childhood lymphoblastic leukemia. Childhood MDS, CML, and AML are often associated with constitutional genetic abnormalities, such as Down s syndrome and Neurofibromatosis type 1 (NF1) syndrome. Inherited predisposition to these myeloid diseases presents the possibility of investigation into the role of specific gene products in regulating myeloid cell growth and differentiation. Preliminary evidence obtained suggests that loss of the NF1 tumor suppressor gene product, neurofibromin, predisposes myeloid cells to leukemic transformation, in part, by causing increased and prolonged Ras activation following growth factor stimulation. This project will test the hypothesis that loss of NF1 expression initiates myeloid leukemia development because neurofibromin normally represses the response of myeloid cells to a cytokine, granulocyte/macrophage-colony stimulating factor (GM-CSF), that can dramatically increase myeloid cell numbers. Furthermore, those signaling pathways, activated by the GM-CSF receptor, which are most important for the phenotypic effects of NF1 gene loss on myeloid cells with be identified. These goals will be met using Nf1 gene-deficient, GM-CSF receptor-deficient mice and immortalized myeloid cell lines derived from these mice. Insights into the mechanisms of deregulation of the GM-CSF signaling pathway by loss of neurofibromin expression is likely to lend insight into fundamental processes of myelodysplastic and myeloproliferative hematopoietic disorders. These insights will suggest hypotheses that will, in part, be tested by the development of therapeutics which target those signaling pathways whose dysregulation is central to the disease phenotype. Thus, a final goal of this proposal is to determine if a novel, tricyclic class of the farnesyl protein transferase (FPTase) inhibitors, which inhibit Ras protein function, show therapeutic potential in several mouse models of MDS/myeloid leukemia with Nf1 gene mutation.