One of the more promising treatments of the myeloid leukemias (AML and CML) is high dose chemotherapy with allogeneic or autologous bone marrow rescue (BMT). Although the disease free survival is higher in patients receiving allogeneic BMT, the majority of patients unfortunately do not have a suitable donor at the time of transplantation. Autologous BMT is complicated by the presence of leukemic cells in the bone marrow harvested for transplantation. Leukemia is the result of disruption of the pathways that regulate cell proliferation. These pathways include mitogenic signals, growth inhibitory signals, and cell survival signals. Preliminary evidence suggests that these latter signals differ between normal cells and cancer cells, as well as between cancers derived from solid tissue cells and hematopoietic cells. We postulate that activation of mitogenic pathways also activates PCD pathways in leukemic stem cells that will provide therapeutic targets. To survive, these cells over express inhibitors of the PCD pathway such as members of the bcl-2 family or c-myb. To test this hypothesis, adenovirus vectors that contain minigenes that encode proteins that functionally inactivate the bcl-2 and c-myb pathways will be used to determine the role of these proteins in protecting normal stem cells and leukemic cells from PCD. Strong preliminary evidence suggests that the Myb oncogene and p53 tumor suppressor proteins physically interact and modulate apoptosis and differentiation. A dominant-negative Myb adenovirus vector induces HEL leukemia cells to undergo apoptosis. Better understanding the role of these proteins in normal and leukemic cell survival and differentiation may lead to better treatment of AML and CML. The following specific aims will address these issues. First, to determine whether recombinant adenovirus vectors can transduce e genes into long term repopulating hematopoietic stem cells. Second, to determine whether adenovirus mediated gene- transduction of normal or leukemic hematopoietic cells is affected by hematopoietic growth factors. Third, to determine the effect of recombinant viral vectors that express a dominant-negative repressor of c-myb or members of the bcl-2 family on the viability of normal and leukemic hematopoietic cells in vitro and in vivo.

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National Cancer Institute (NCI)
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University of Michigan Ann Arbor
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