The molecular control of hematopoiesis: From clonal development in culture to therapy in the clinic

Abstract

The establishment of a cell culture system for the clonal development of hematopoietic cells has made it possible to discover the proteins that regulate cell viability, growth and differentiation of different hematopoietic cell lineages and the molecular basis of normal and abnormal cell development in blood‐forming tissues. These regulators include cytokines now called colony stimulating factors and interleukins. Different cytokines can induce cell viability, multiplication and differentiation, and hematopoiesis is controlled by a network of interactions between these cytokines. This network includes positive regulators such as colony stimulating factors and interleukins and negative regulators such as transforming growth factor β and tumor necrosis factor. Gene cloning has shown that there is a family of different genes for these cytokines. The functioning of the network requires an appropriate balance between positive and negative regulators and the selective regulation of programmed cell death (apoptosis). There are different ways of inducing or inhibiting programmed cell death, and differences in the regulation of this program can result in tumor promotion or tumor suppression. 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. A network may also be necessary to stabilize the whole system. Cytokines that regulate hematopoiesis can induce the expression of genes for transcription factors. Interaction between cytokines and transcription factors can thus ensure the autoregulation and transregulation of cytokine genes that occur in the network. Normal protein regulators of hematopoiesis can control the abnormal growth of certain types of leukemic cells and suppress malignancy by inducing differentiation to mature nondividing cells. Genetic abnormalities that give rise to malignancy in these leukemic cells can be bypassed and their effects nullified by inducing differentiation, which stops cells from multiplying. Hematopoietic regulatory cytokines are active in culture and in vivo and have been used clinically to correct defects in blood cell development in patients with various abnormalities including cancer. The results provide new approaches to therapy. The existence of a network and the ability of cytokines to regulate programmed cell death have to be taken into account in the clinical use of cytokines for therapy.