The molecular control of hemopoiesis and leukemia

Abstract

The establishment of a cell culture system for the clonal development of hemopoietic cells made it possible to discover the proteins that regulate cell viability, growth and differentiation of different hemopoietic 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 hemopoiesis is controlled by a network of cytokine interactions. This multigene network includes positive regulators such as CSFs and ILs and negative regulators such as transforming growth factor beta and tumor 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 p53, c-myc and bcl-2, and suppression or induction of this program can result in tumor promotion or tumor suppression. Cytokines that regulate normal hemopoiesis can control the abnormal growth of certain types of leukemic cells and suppress malignancy by inducing differentiation. Genetic abnormalities that give rise to malignancy in these leukemic cells can be by-passed and their effects nullified by inducing differentiation and programmed cell death. The hemopoietic cytokines discovered in culture are active in vivo and are being used clinically to correct defects in hemopoiesis.