THE MOLECULAR CONTROL OF HEMATOPOIESIS AND LEUKEMIA

The establishment of a cell culture system for the clonal development of hemopoietic cells made it possible to discover the proteins that re gulate cell viability, growth and differentiation of different hemopoi etic cell lineages and the molecular basis of normal and abnormal deve lopment in blood-forming tissues. These regulators include cytokines n ow called colony stimulating factors (CSFs) and interleukins (ILs). Di fferent cytokines can induce cell viability, multiplication and differ entiation, and hemopoiesis is controlled by a network of cytokine inte ractions. This multigene network includes positive regulators such as CSFs and ILs and negative regulators such as transforming growth facto r beta and tumor necrosis factor. The cytokine network which has arise n during evolution allows considerable flexibility depending on which part of the network is activated and the ready amplification of respon se to a particular stimulus. The CSFs and ILs induce cell viability by inhibiting programmed cell death (apoptosis). Programmed cell death i s 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 pr omotion or tumor suppression. Cytokines that regulate normal hemopoies is can control the abnormal growth of certain types of leukemic cells and suppress malignancy by inducing differentiation. Genetic abnormali ties that give rise to malignancy in these leukemic cells can be by-pa ssed and their effects nullified by inducing differentiation and progr ammed cell death. The hemopoietic cytokines discovered in culture are active in vivo and are being used clinically to correct defects in hem opoiesis.