The molecular control of haemopoiesis and leukaemia

Abstract

The establishment of a cell culture system for the clonal development of haemopoietic cells made it possible to discover the proteins that regulate cell viability, growth and differentiation of different haemopoietic cell lineages and the molecular basis of normal and abnormal development in blood-forming tissues. These regulators include cytokines now called colony stimulating factors (CSFs) and interleukins (ILs). Different cytokines can induce cell viability, multiplication and differentiation, and haemopoiesis is controlled by a network of cytokine interactions. The multigene network includes positive regulators such as CSFs and ILs and negative regulators such as transforming growth factor β and tumour necrosis factor. The cytokine network which has arisen during evolution allows considerable flexibility depending on which part of the network is activated and the ready amplification of response to a particular stimulus. The CSFs and ILs induce cell viability by inhibiting programmed cell death (apoptosis). Programmed cell death is also regulated by the genes wild-type and mutant p 53, c-myc and bcl-2, and suppression or induction of this programme can result in tumour promotion or tumour suppression. Cytokines that regulate normal haemopoiesis can control the abnormal growth of certain types of leukaemic cells and suppress malignancy by inducing differentiation. Genetic abnormalities that give rise to malignancy in these leukaemic cells can be by-passed and their effects nullified by inducing differentiation and programmed cell death. The haemopoietic cytokines discovered in culture are active in vivo and are being used clinically to correct defects in haemopoiesis.