The goal of the proposed research is to learn more about the pathogenesis, natural history and treatment of human hemopoietic neoplasms by using the naturally occurring cellular mosaicism found in females heterozygous for the enzyme glucose-6- phosphate dehydrogenase (G6PD) or for a DNA marker such as a variant in the nucleotide sequence of hypoxanthine phosphorbosyl transferase (HPRT). Normal and abnormal hemopoietic and other cells will be studied directly and previously described methods will be used to grow hemopoietic cells in long-term marrow cultures, lymphocyte suspension cultures and in semi-solid media (as colonies).
Specific aims of the proposed research include: 1) To investigate heterogeneity of acute nonlymphocytic leukemia (ANLL) in differentiative expression of the involved stem cells, in the pattern of remissions and in antigenic characteristics of leukemic progenitors. 2) To use monoclonal antibodies to enrich normal progenitors and eliminate leukemic progenitors by a combination of positive and negative selection for the normal and abnormal progenitors, respectively. 3) To substantiate the hypothesis that chronic myelogenous leukemia (CML) and many ANLLs have a multistep pathogenesis in which clonal proliferation of genetically unstable pluripotent stem cells antedates the development of characteristic cytogenetic abnormalities such as the Philadelphia chromosome (Ph). 4) To demonstrate the the Ph- negative cells that appear in CML patients treated with recombinant alpha interferon (IF alpha) are in fact normal nonclonal progenitors and that the in vivo response to IF alpha can be predicted from the response in long-term culture. 5) To document the suggestions that Simian virus 40 (SV40)-transformed marrow stromal (""""""""microenvironmental"""""""") cells in long-term marrow cultures can be grown as colonies in semi-solid media and that they share a common stem cell with hemopoietic progenitors. 6) To characterize the differentiation antigenic phenotype of the pre-colony-forming cell we recently identified in marrow long- term cultures and to demonstrate that it is pluripotent for the lymphoid as well as the myeloid lineages. It is hoped that the results of the proposed work will contribute to the understanding of human leukemogeneis and to attainment of the goal of preventing the malignancies or providing a basis for rational therapy. One potential application of the ability to distinguish normal from leukemic progenitor cells and to selectively eliminate the latter cells is the treatment in vitro of remission marrow cells from patients with ANLL prior to autologous transplantation.
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