The goal of the proposed research is to use the naturally occurring cellular mosaicism found in women heterozygous for the enzyme glucose-6-phosphate dehydrogenase (G6PD) to learn about the development and treatment of human tumors, with emphasis on hemopoietic neoplasms. Normal and abnormal cells will be studied directly and previously described methods will be used to grow normal and abnormal hemopoietic cells in long-term marrow cultures, lymphocyte suspension cultures, and as colonies in semi-solid media. Specifically, aims of the proposed research include: 1) Definitiion of the hierarchal stem cell level involved by chronic myelocytic leukemia (CML), other myeloproliferative disorders (MPDs) and acute nonlymphocytic leukemia (ANLL). 2) Documentation that marrow """"""""microenvironmental"""""""" cells in vitro emanate from this pluripotent stem cell, that they can be grown in vitro as colonies and that they play a role in the pathogenesis of some cases of hemopoietic neoplasia or aplastic anemia. 3) Evidence will be sought to substantiate the postulate that hemopoietic neoplasms develop through a multistep process in which currently detectable chromosome abnormalities occur after an initial step(s) leading to clonal proliferation of genetically unstable pluripotent stem cells. 4) Heterogeneity in stem cell differentiative expression, remissions and antigenic characteristics of leukemic progenitors from patients with ANLL will be investigated. 5) Attempts will be made to selectively eliminate leukemic progenitors in mononuclear cell preparations from patients with ANLL by physical means or lysis by monoclonal antibodies directed against myeloid differentiation antigens. Through these means it is hoped that the proposed work will contribute to the understanding of leukemogenesis and the role of such factors as chromosomal abnormalities and oncogenes. The ultimate goal of elucidating the mechanism of leukemogenesis is to provide a basis for its prevention or rational therapy. For example, ability to distinguish definitively normal from abnormal hemopoietic progenitors in patients with ANLL allows studies of methods to selectively eliminate the abnormal progenitors, such as with monoclonal antibodies or physical separations. One potential application may be in the in vitro treatment of remission marrow cells from patients with ANLL before storage for subsequent autologous transplantation.
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