The Wellcome Foundation lecture, 1986. The molecular regulators of normal and leukaemic blood cells.

Abstract

The development of a cell-culture system for the cloning and clonal differentiation of different types of blood cell has made it possible to identify: (i), the proteins that regulate growth and differentiation of different cell lineages in normal and leukaemic blood cells; (ii), the molecular basis of normal and abnormal control of cell development in blood-forming tissue; and (iii), how to suppress malignancy in leukaemic cells. By using myeloid blood cells as a model system, it has been shown that normal blood cells require different proteins to induce cell viability and multiplication (growth-inducers) and differentiation (differentiation-inducers), that there is a hierarchy of growth-inducers which act at various stages of cell development, and that a growth-inducer can switch on production of a differentiation-inducer. Gene cloning has established a multigene family for these proteins. Identification of these proteins and their interaction has shown how growth and differentiation are regulated in normal development and demonstrated the mechanisms that uncouple growth and differentiation so as to produce malignant cells. Normal cells require an external source of growth-inducing protein for cell viability and multiplication. Cells can become leukaemic by genetically changing this normal requirement for growth without blocking response to normal differentiation-inducers. The mature cells induced by adding these normal protein-inducers are then no longer malignant. Other genetic changes which inhibit differentiation by the normal blood-cell regulatory proteins can occur in the evolution of leukaemia. But even these leukaemic cells may still be induced to differentiate by other compounds that can induce differentiation by alternative pathways. The differentiation of leukaemic to mature cells, which stops the cells from multiplying, results in the suppression of malignancy by bypassing genetic changes that produce the malignant phenotype. The activity of blood-cell growth- and differentiation-inducing proteins has been shown in culture and in the body. They can, therefore, be clinically useful to correct defects in the development of normal and leukaemic blood cells.