Chronic myelogenous leukemia (CML) results from the transformation of a very primitive hematopoietic cell by the BCR/ABL oncogene and is characterized by increased myeloproliferation and abnormal trafficking of malignant progenitors. CML progenitors demonstrate several abnormalities in hematopoietic regulation including increased growth factor-induced proliferation, reduced adhesion to fibronectin and reduced chemotaxis towards SDF-1a. Although the tyrosine kinase inhibitor imatinib mesylate is very effective in the treatment of CML, elimination of malignant progenitors is often incomplete and clinical resistance can occur. Therefore, additional treatment approaches to target BCR/ABL activated signaling mechanisms important for transformation are of high priority. The contribution of different BCR/ABL mechanisms to transformation varies from 1 cell type to the other, and the contribution of known mechanisms to human hematopoietic cell transformation is not clear. The goal of the proposed studies is to investigate molecular mechanisms that are critical for human progenitor transformation. In preliminary studies, we have investigated abnormalities in intracellular signaling in CD34+ progenitor cells from CML patients. We have also developed a novel CML model based on ectopic expression of the BCR/ABL gene in human CD34+ cells, which reproduces abnormalities in hematopoietic regulation seen in primary CML progenitors and facilitates study of molecular mechanisms of transformation. Preliminary studies have identified BCR/ABL protein domains that may significantly contribute to abnormal progenitor growth and adhesion.
In Specific Aim 1 we will investigate the role of an autophosphorylation site at BCR Y177 and downstream signaling through Grb2, Gab2 and Shp2 in abnormal proliferation and apoptosis of BCR/ABL expressing human progenitors.
In Specific Aim 2 we will investigate the mechanisms of abnormal adhesion and chemotaxis in BCR/ABL transformed human progenitors. Finally, in Specific Aim 3 we will investigate whether inhibition of the above signaling pathways can enhance suppression of CML progenitors growth when combined with imatinib, and/or can suppress growth of progenitors resistant to imatinib because of kinase domain mutations. These studies are expected to result in improved understanding of mechanisms critical for human progenitor transformation in CML and guide rational development of additional mechanism-based therapies.
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