Normal hematopoiesis of the myeloid and/or B-cell lineage is disrupted in Ph-positive leukemia through the activity of the Bcr/Abl P210 or P190 proteins. BCR/ABL is generated through the illegitimate fusion of the BCR and ABL genes. The molecular genetics of these genes is well-understood but we do not know why the two forms of Bcr/Abl cause only leukemia, why P210 and P190 differ in their transforming potency, nor have the pathways through which the fusion proteins cause tumorigenesis in vivo been elucidated. The investigators hypothesize that the specificity for transformation of hematopoietic cells and the different activities of Bcr/Abl P210 and P190 are conferred by the BCR moiety, through regulatory action on members of the Rho family of proteins. To investigate this, the investigators will analyze in vitro and in vivo activities and interactions of Bcr and its cognate ABr with members of the Rho family and with other hematopoietic proteins. They have identified and cloned the adaptor- signaling molecule Crkl as a specific major substrate for the tyrosine kinase activity in Bcr/Abl. The investigators hypothesize that tyrosine-phosphorylation of Crkl by Bcr/Abl in hematopoietic cells disturbs its normal function, leading to leukemogenesis. Experiments aimed at determining the cell type in and physiological stimulus under which tyrosine phosphorylation is normal for Crkl and the effect of tyrosine phosphorylation on the ability of Crkl to bind other proteins are proposed. The investigators will also determine the ability of a tyrosine phosphorylation-negative Crkl mutant, Y207F, to transform cells, to relocate to a different cellular compartment or to alter transforming ability of Bcr/Abl in cultured cells and in vivo in BCR/ABL P190 transgenic mice. These experiments are designed to determine why BCR/ABL is only associated with tumors of the hematopoietic system and will identify key steps in the process of leukemogenesis. In addition, signaling pathways important for normal hematopoiesis will be distinguished. These results relate directly to the long-term objective of understanding the development of Ph-positive leukemia in sufficient detail to allow for a cure of this malignancy.
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