The tyrosine kinase activity of the ABL oncogene is a growth stimulus for hematopoietic cells. ABL is activated by viral transduction in the Abelson murine leukemia virus GAG-ABL fusion and in human leukemias with the Philadelphia chromosome translocation, including chronic myelogenous leukemia and acute lymphocytic leukemia, which generate BCR-ABL fusions. The overall goal of this proposal is to understand the roles of ABL in the growth regulation of hematopoietic stem cells and in the pathogenesis of leukemia. We will expand upon our successful development of hematopoietic tissue culture and in vivo models for leukemogenesis which have helped to define the target cells for the ABL gene. Further definition of the structural changes and functional consequences of the activation of the ABL tyrosine kinase activity, and their relation to cellular signalling pathways, will be carried out. The role of the BCR gene in the transcriptional, translational, and posttranslational control of expression and function of the ABL gene in human leukemias will be studied. Interactions of ABL with other oncogenes and growth factor systems will be evaluated in culture and animal models to understand the progression of human chronic myelogenous leukemia to the blast crisis phase. Continued studies on the pathobiology of Ph positive leukemias in the human host and their response to treatment will be done. We will modify current polymerase chain reaction technologies to allow more quantitative evaluation of residual tumor burden and its clinical implications, especially in the post-bone-marrow-transplant setting. The growth characteristics of populations of human chronic myelogenous leukemia cells at different stages of disease progression will be evaluated in the SCID mouse model. Interactions between hematopoietic elements and bone marrow derived stromal elements will be tested in a manner that recapitulates the architecture of marrow. We hope to be able to effectively grow the stem cells of this leukemia in this special environment, and potentially learn much about the nature of normal and abnormal stem cell growth regulation.
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