The goals of this research program are to characterize primitive hematopoietic cells with a capacity for self renewal (CFU-B1) in normal individuals and those with acute non lymphocytic leukemia (A.N.L.L.) and myeloproliferative disorders (M.P.D.). Normal CFU- B1 will be phenotyped using monoclonal antibodies and complement mediated cytotoxicity or flow cytometry. Cell cycle analysis of CFU-B1 will be performed and sensitivity of these primitive hematopoietic cells to in vitro treatment with chemotherapeutic drugs will be determined. The dependence of GPU-B1 on hematopoietic growth factors such as human Il-3, GM-CSF, and Il-1 acting alone or in combination will be determined. long term marrow culture systems will be utilized in order to determine the ability of CFU-B1 to initiate sustained hematopoiesis and the role of marrow adherent cells in regulation of the CFU-B1. Murine monoclonal antibodies will be produced to further characterize human CPU-B1. A sequence of steps to isolate CPU-B1 will be developed in order that pure population of CFU-B1 will be obtained. These pure population of CPU-B1 will be utilized in order that humoral and cellular influences on the maintenance, proliferation, commitment and differentiation of this primitive hematopoietic cell will be better defined. Once the normal CFU-B1 is characterized the role of this primitive hematopoietic cell in leukemogenesis will be examined. For this purpose, CFU-B1 obtained from individuals with A.N.L.L. and those with various M. P. D. such as polycythemia vera, chronic granulocytic leukemia and primary thrombocytosis will be studied. Immunological and biological behavior of A.N.l.l. and M. P. D. CFU-B1 will be studied in order to determine the consequences of leukemogenesis at this very primitive cellular level. The mechanism of achievement of chemotherapy induced remission in A.N.L.L. will also be approached by attempting to detect the presence of quiescent leukemic CFU-B1 that might ultimately be responsible for relapse. The availability of new cell biological systems will permit the examination of early events that occur during normal and leukemic hematopoiesis. The use of recombinant growth factors and purified cellular populations offer the promise that a sophisticated cellular biological approach will make an impact on expanding our understanding of these potentially clinically relevant processes.
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