The long-term aim of this work is to understand the cellular and molecular mechanisms which regulate hemopoietic cell differentiation in the normal state and in abnormalities occurring in leukemias. The experiments described are designed to exploit our preliminary studies and explore the mechanisms by which hemin, a regulator of erythropoiesis, and aclacinomycin, an anthracycline, are able to convert human K-562 leukemic hemopoietic cells into cells resembling normal blood cells. We will: (1) determine whether hemin interacts either directly or indirectly with nuclear components involved in the transcription of DNA; (2) demonstrate whether treatment of K-562 cells with both hemin and aclacinomycin promotes commitment to erythroid maturation and induces adult hemoglobin synthesis (hemin alone induces only embryonic and fetal globin synthesis and fails to promote terminal erythroid maturation of K-562 cells in culture); and (3) investigate the possible ways by which hemin counteracts the antiproliferative action of adriamycin on normal and leukemic hemopoietic cells. Information obtained from these studies should define the nature of interactions between hemin and nuclear components which may be pivotal to the activation of globin genes during erythroid cell maturation. It will help to determine whether chemical inducers of hemopoietic cell differentiation such as hemin can be used effectively either alone, or in combination with other agents, for the reversion of the malignant state and for protection of the bone marrow from cytotoxic effects. (M)
