THE HEMATOPOIETIC EFFECTS OF GROWTH-HORMONE AND INSULIN-LIKE GROWTH-FACTOR-I

The process of haemopoiesis, occurring primarily within the bone marro w, involves the proliferation and differentiation of pluripotent haemo poietic stem cells into committed, or pathway-restricted progenitors / 1/. The latter further proliferate and undergo a process of maturation into circulating blood cells of myeloid and erythroid lineages /2/. H aemopoietic cell growth and differentiation is primarily regulated by the local production of various cytokines within the bone marrow micro -environment /3/, as well as by the circulating hormone, erythropoieti n (EPO). The formation as well as functional activation of mature bloo d cells, are also modulated by a variety of hormones and growth peptid es, including growth hormone (GH) and insulin-like growth factor-I (IG F-I) /4,5/. Early evidence for the role of GH in modulating haemopoies is was provided in classical studies in rodents, which showed that rem oval of the pituitary gland affects blood cell formation and function /6/ and that impairment of the latter can be restored by GH administra tion /7/. GH exerts its effects on target cells by binding to its own receptor, which belongs to the class I cytokine receptor superfamily / 8/. In humans, GB can also bind to and activate the prolactin receptor /9/. Based on the somatomedin hypothesis of Salmon and Daughaday /10/ , it is now generally accepted that, in addition to the above, GH exer ts many of its effects via autocrine or paracrine IGF-I, as well as vi a endocrine IGF-I produced in the liver. IGF-I, a small single-chain p olypeptide, is one of two highly homologous peptides (IGF-I and IGF-TI ), that stimulate the proliferation and differentiation of a wide vari ety of cell types, including bone marrow cells /5,11/. Both ICF-I and IGF-II play an important role in prenatal growth and IGF-T is also ess ential for postnatal growth and development /12/. Two types of IGF rec eptors have been described. The type I IGF receptor, a tyrosine kinase receptor highly homologous to the insulin receptor, binds IGF-I and I GF-II with a high affinity. The type II/mannose 6-phosphate receptor w hich lacks intrinsic kinase activity, binds IGF-II with a high affinit y and IGF-I with a low affinity /13,14/. Haemopoietic progenitors and mature blood cells have been shown to produce GH and IGF-I and to expr ess receptors for these peptides. GH and IGF-I may act independently o n these cells or, as more commonly observed, in a synergistic manner w ith primary haemopoietic cytokines. GH and IGF-I receptors are also pr esent on freshly explanted leukemic cells and leukemic cell lines. Thu s, their possible contribution to the development of leukemia should a lso be considered. This review summarizes our current understanding of the role of GH and IGF-I in normal and malignant haemopoiesis.