Hematopoietic growth and differentiation factors and the reversibility of malignancy: cell differentiation and by-passing of genetic defects in leukemia.

Our development of systems for the in vitro cloning and clonal differentiation of normal hematopoietic cells made it possible to identify: the factors that regulate growth and differentiation of these normal cells; the changes in the normal development program that result in leukemia, and how to reverse malignancy in leukemic cells. I have mainly used myeloid cells as a model system. Normal hematopoietic cells require different proteins to induce growth (growth factors) and differentiation (differentiation factors). There is a multigene family for these factors. Identification of these factors and their interaction has shown how growth and differentiation can be normally coupled. The development of leukemia involves the uncoupling of growth and differentiation. This can occur by changing the requirement for growth without blocking cell response to the normal inducers of differentiation. Addition of normal differentiation factors to these malignant cells still induces their normal differentiation, and the mature cells are then no longer malignant. Genetic changes which inhibit differentiation by normal differentiation factors can occur in the progression of leukemia, but even these leukemic cells may still be induced to differentiate by other compounds, including low doses of compounds now being used in cancer therapy, that can induce differentiation by alternative pathways. The differentiation of leukemic to mature cells results in the reversion of malignancy by by-passing genetic changes that produce the malignant phenotype. We have obtained this differentiation of leukemic cells in vitro and in vivo, and by-passing genetic defects by inducing differentiation can be a useful approach to therapy.