Studies on differentiation inducing factors for human myelogenous leukemic cells and enhancement of their activity.

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Human myelogenous leukemic cells can be induced to differentiate into the monocyte/macrophage pathway by various chemicals and protein inducers called differentiation inducing factors(DIF). However, human DIF has not yet been well characterized. We have tried to purified DIFs from eadia conditioned by PHA-stimulated lymphocytes and fibroblasts in this project.We have succeeded to purify a DIF homogeneity from lymphocyte conditioned medium. The purified DIF has a relative molecular mass of approximately 17,000, with an NH_2-terminal sequence the same as that of human tumor necrosis factor(TNF). We have also succeeded to purigy a fibroblast-derived differentiation inducing factor(F-DIF) from medium conditioned by a human fibroblast cell line(WI-26VA4). The purified DIF had a molecular weight of about 27,000 determined by SDS-PAGE, with an HN_2-terminal sequence the same as that of human interleukin-6(IL-6) except for the absence of the N-terminal proline. F-DIF synergistically induced differentiation of human myelogenous leukemic cell lines when combined with TNF.F-DIF synergistically enhanced the differentiation of human myelogenous leukemic cell lines when combined with TNF. TNF and IL-6 synergistically enhanced the differentiation in combination with other biological response modifiers such as prostaglendin E_2, retinoic acid, vitamid D_3, interferon- , etc.The results presented in this project point to another new biological effects of TNF and IL-6. This could be one of the regulatory signals that control cellular reactions during infection. Combination use of cytokines and BRM may play in effecting terminal differentiation of the clinical leukemias.