Children with the common inherited disorder neurofibromatosis, type 1 (NF1) are predisposed to myeloid leukemia, particularly juvenile chronic myelogenous leukemia (JCML). The NF1 gene (NF1) encodes a protein called neurofibromin that stimulates the GTPase activity of the p21 ras (Ras) family of signaling proteins. This activity of neurofibromin suggested that NF1 might function as a tumor-suppressor gene in myeloid cells by negatively regulating Ras. Genetic and biochemical data from the laboratory support this hypothesis. The investigators have developed a murine model to investigate the role of NF1 in myeloid growth control. This translational research project is based on laboratory data which suggest that deregulated signaling through the Ras pathway in response to granulocyte macrophage colony stimulating factor (GM-CSF) plays a central role in the over-proliferation of myeloid cells that is characteristic of murine NF1-/- fetal liver cells and JCML bone marrow cells. This proposal has 3 specific aims. The experiments proposed under aim 1 will provide a rigorous genetic test of the hypothesis that the deregulated growth of NF1-/- cells is GM-CSF-specific. The experiments proposed in aim 2 are based on genetic and biochemical evidence that hyperactive Ras plays a central role in the aberrant phenotype of murine Nf1-/- and human JCML cells. These mechanistic data suggest that drugs that target the Ras pathway are rational potential theraeputics for JCML and other myeloid leukemias. Mice reconstituted with Nf1-/- fetal liver cells provide a genetically-defined in vivo model system to test this hypothesis. The third experimental aim will involve characterizing the germ line and somatic NF1 mutations that exist in children with leukemia as these data may provide novel insights into mechanisms of normal growth control and tumorigenesis.
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