We have identified two significant defects related to differentiation of leukemia cells in untreated acute myelogenous leukemia (AML) patients. The first is a deficiency in the number of T cells which produce the differentiation factor """"""""maturation inducer"""""""", as compared to healthy persons. The second defect, demonstrated in our preliminary experiments, is a significantly lower serum level of maturation inducer in leukemia patients. this maturation inducer is a lymphokine which mediates the terminal differentiation of human myeloid leukemia cells to monocytes and macrophages. It has been purified as a single polypeptide chain of 54 kDa; its partial amino acid sequence and antibodies have been obtained. We have also found that leukemia cells only differentiate with an optimal concentration of the maturation inducer. Abnormal quantities of the maturation inducer resulted in enhanced growth of leukemia cells, indicating the importance of physiological levels of maturation inducer in the disease.
Our aim i s to better define the differentiation defects of myeloid leukemia cells and to investigate the usefulness of the maturation inducer and its cells to correct these defects. The abnormalities in serum levels of maturation inducer and in the number of T cells producing it in leukemia will be demonstrated using patients having different disease status and treatment variables. the percentage and absolute number of these T cells will be determined with flow cytometry using anti-maturation inducer antibody; serum levels of the inducer will be determined using a sandwich enzyme assay. A correlation will be made between these two deficiencies. We also aim to isolate these T cells using a positive antibody panning procedure, and to characterize them with regard to morphology, phenotype, and proliferation response to mitogenic and antigenic stimulation etc. The isolated cells will be cultured with IL2, and analyzed for subsequent use in adoptive immunotherapy. The efficacy of the maturation inducer as a therapeutic will be investigated as a long-term goal. We will obtain the recombinant form of the maturation inducer by cloning the molecule from a producing T cell line, using a papilloma virus vector. The maturation inducer can then be evaluated using a differentiation assay with leukemia cells from cell lines and patients. The response potential of leukemia cells will be analyzed by specific binding studies using 125I- maturation inducer. The proposed studies will further our understanding of basic pathogenic processes in leukemia and may very well lead to a practical method for controlling the differentiation deficiency of these cells.
| Chiao, J W; Hsieh, T C; Xu, W et al. (1999) Development of human prostate cancer cells to neuroendocrine-like cells by interleukin-1. Int J Oncol 15:1033-7 |
