The overall objective of this proposal is to delineate the mechanisms associated with Bcr-Abl-induced leukemogenesis. Previous studies have identified two Abl interactor (Abi) proteins, Abi-1 and Abi-2, that bind to cellular Abl (c-Abl) and are substrates of Abl tyrosine kinase. Abi-1 is tyrosine-phosphorylated in hematopoietic cells transformed by Bcr-Abl. Recent studies indicate that Abi-1 is a key regulator of Rac signaling, a pathway important for regulation of hematopoietic cell migration and homing. Abi-2, on the other hand, is degraded in Bcr-Abl-expressing hematopoietic cells. The expression of Abi-2 is lost in cell lines and bone marrow cells isolated from patients with aggressive Bcr-Abl-positive leukemia. This proposal is based on the hypothesis that the signal transduction from Bcr-Abl to Abi-1 and Abi-2 may play an important role in Bcr-Abl-induced leukernogenesis. We postulate that the tyrosine phosphorylation of Abi-1 and subsequent activation of Rac pathway may represent an important mechanism by which Bcr-Abl induces abnormalities of cytoskeletal function and metastatic phenotype in leukemic cells. We believe that loss of Abi-2 may be a component in the progression of Bcr-Abl-positive leukemia. The goals of this proposal, therefore, are to examine the leukemogenic potential of a mutant Bcr-Abl that is defective in signaling to Abi-1 and Abi-2; to determine the role of Abi-1 and Abi-2 in Bcr-Abl-induced leukemogenesis; and to define the mechanisms by which Bcr-Abl regulates Abi signal transduction. To achieve these goals, biochemical and genetic approaches are designed to disrupt or inactivate signal transduction of Abi-1 and Abi-2 in hematopoietic system. Bone marrow transplant mouse models will be employed to evaluate the effect of disruption of Abi signaling on Bcr-Abl-induced leukemogenesis. Sequences in Abi-1 and Abi-2 that are critical for regulation of signal transduction will be defined and mutations wilt be made for functional analysis. Collectively, these studies may provide insight into the regulatory mechanisms of cell migration, homing, and metastasis. Understanding the role of Abi signaling in neoplastic hematopoiesis should shed light on development of more effective therapies for the treatment of human leukemia.
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