The understanding of the role of human interleukin-3 (IL-3) in the pathogenesis of leukemias and the use of this information for design of new therapeutic strategies is the long term objective.
The specific aims are - 1. Definition of the biologic spectrum of activities of the newly discovered recombinant hIL-3 molecule. This will involve its effects on bone marrow, including potential for self-renewal and capacity for differentiation, as well as activation of mature cells. 2. The capacity of myeloid leukemic cells to respond to hIL-3 will be examined in a clonogenic assay. It is hypothesized that some leukemic cells will respond to IL-3 by differentiation (hence loss of clonogenic potential) while for others IL-3 will be essential for self-renewal. The response to IL-3 will help not only in providing a potentially useful basis for classification but also in indicating a rationale for use in therapy. 3. The number and affinity of receptors on normal bone marrow, mature or leukemic cells, will be estimated by radiolabelled ligand binding and the interaction of IL-3 with other colony- stimulating factors will also be addressed. 4. Chemical synthesis of the IL-3 molecule will be undertaken in order to explore regions of the molecule essential for function and then this information will be used to raise monoclonal antibodies against critical peptide segments. These peptides will be examined for biological function and subsequently for raising anti- idiotypes as possible probes for the IL-3 receptor. 5. The cDNA probe for hIL-3 will be used for defining the cellular source of IL-3. The study will be undertaken in bulk cell populations of normal and leukemic cells and also in in-situ hybridization to give precise anatomical localisation of the cells in question. These studies will give substantial information as to which cells have receptors and can respond to IL-3 and provide data on whether an abnormality of either production or responsiveness exists in myeloid leukemias and point to the type of leukemia in which therapeutic strategies may be most effective.
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