Haemopoietic growth factors

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Haemopoiesis, 303

The role of haemopoietic growth factors in normal haemopoiesis, 303 Growth factor receptors, 303 Signal transduction by growth factor receptors, 305

Jak/STAT signalling, 305 Ras-dependent signalling, 305 Recombinant growth factors, 305

Erythropoietin, 305

Granulocyte and granulocyte-macrophage colony-stimulating factors, 308

Long-acting haemopoietic growth factors, 315

Thrombopoietin, 315 Stem cell factor, 315 Interleukin 3, 316

Chimeric haemopoietic growth factors, 316 Selected bibliography, 316

Haemopoiesis

Stable haemopoiesis is maintained by the activity of pluripoten-tial stem cells, which are capable not only of differentiating to form all three haemopoietic cell lineages, but also of retaining the ability for self-renewal. These pluripotential stem cells give rise to more differentiated lineage-committed stem cells that in turn differentiate into mature blood cells.

Initially, measurements of the stem cell content of human bone marrow could only be inferred by the growth of erythroid, myeloid and megakaryocytic cell colonies (BFU-E, CFU-GM and CFU-Meg) in culture. It has been estimated that there are 1 X 106 pluripotential stem cells in human marrow, and assays for these primitive cells have been developed, such as the long-term culture-initiating cell (LT-CIC) assay. In 1984, the expression of a specific antigen (now designated the CD34 antigen) on the surface of a small percentage of immature marrow cells was identified. This CD34+ fraction of cells does, in fact, contain a number of committed stem cells, but it is also capable of restoring haemopoiesis following myeloablative chemotherapy, indicating that it also contains the pluripotential cell fraction. Expression of the CD34 antigen appears to be stage specific and is lost upon further maturation. Studies have shown that cells expressing high levels of CD34 are the most primitive, and those with a CD34bright, Thy-1+, CD38-, CD45RO+ and rhodaminedui profile are representative of true pluripotential stem cells and account for less than 10% of the CD34+ cell fraction.

The survival, differentiation and proliferation of haemopoietic progenitor cells in vivo and in vitro are dependent on the presence of small, hormone-like polypeptide molecules referred to as haemopoietic growth factors or colony-stimulating factors (CSFs). A large number of these factors have now been cloned and their effects have been studied. Their effects are exerted upon cells following interaction with specific growth factor receptors situated on the cell surface, which in turn activate signal transduction pathways. Different CSFs act on bone marrow cells at different stages of maturation (Table 18.1). Some influence immature progenitors and increase the production of cells of several lineages [e.g. interleukin 3 (IL-3) and stem cell factor (SCF)], whereas others act on more committed progenitors and thus have a specific effect, leading to an increased production of cells of a particular subtype, e.g. Epo and granulocyte colony-stimulating factor (G-CSF). The evolutionary importance of these molecules is indicated by the significant homology that exists between the species for these growth factors and their receptors and the common use of certain receptor subunits and signalling pathways.

In addition, there is considerable overlap between the functions of different CSFs, for example IL-3, granulocyte-macrophage colony-stimulating factor (GM-CSF) and G-CSF all stimulate the production of mature neutrophils. This redundancy may arise because different CSFs act on cells at different stages of differentiation. Furthermore, the actions of CSFs may be subtly different in that some may promote survival of cells by inhibiting apoptosis, whereas others act to induce proliferation of these cells. There is also evidence that the actions of CSFs may be synergistic in their effects upon haemopoietic progenitors; for example, the addition of SCF and GM-CSF results in an increase in both the number of colonies formed and the number of cells in each colony.

Growth factor receptors

Haemopoietic growth factors act by binding to specific receptor molecules on the surface of haemopoietic progenitors. The

The role of haemopoietic growth factors in normal haemopoiesis

Table 18.1 Haemopoietic growth factors and their receptors.

Growth factor Location of gene Receptor

Cell source

Cells produced

Clinical use

IL-3

5q23-3l

GM-CSF 5q23-3l

G-CSF 17q21-22

l2q22-24

7q21

3q26-27

Low-affinity a-subunit (70 kDa) and ß-subunit (120 kDa) common to IL-3/5 receptors

Low-affinity a-subunit (70 kDa) and ß-subunit (120 kDa) common to IL-3/5 receptors

Low-affinity monomer, high-affinity oligomer

145-kDa transmembrane protein

166-amino-acid polypeptide

Fibroblasts, mast cells, T cells, NK cells, endothelial cells

Fibroblasts, T cell macrophages, marrow stroma, endothelial cells

Fibroblasts, marrow stroma, endothelial cells

Fibroblasts, marrow stroma, endothelial cells

Kidney cells

Product oí c-mpl proto- Liver and kidney oncogene cells

Granulocytes, monocyte/macrophages, eosinophils, basophils, mast cells (erythrocytes if Epo also present)

Granulocytes, monocyte/macrophages, eosinophils, megakaryocytes

Granulocytes

Granulocytes, monocyte/ macrophages, erythrocytes, megakaryocytes

Erythrocytes, megakaryocytes

Megakaryocytes

Not in clinical use

Stem cell mobilization; post chemotherapy/bone marrow transplantation, use in graft rejection

Stem cell mobilization, post-chemotherapy/bone marrow transplantation

? Increase stem cell mobilization

Renal anaemia, MDS; anaemia secondary cancer

Not in clinical use molecular structure of a number of these growth factor receptors is now defined (Figure 18.1).

Some of the receptors have intrinsic tyrosine kinase domains that are activated upon ligand binding to the extracellular domain. Examples include the macrophage colony-stimulating factor (M-CSF) and SCF receptors.

The remaining CSF receptors all share a common Trp-Ser-X-Trp-Ser motif (where X can be any amino acid) near the transmembrane domain and are referred to as part of the cytokine receptor superfamily. Some of these receptors consist of a single chain, for example Epo and G-CSF receptors, whereas others are made up of two or more subunits, some of which are

Cytokine receptor superfamily Protein tyrosine-containing

Cytokine receptor superfamily Protein tyrosine-containing

Figure 1S.1 Cytokine receptor superfamily.

common to several receptors, for example the common subunit of GM-CSF and IL-3 receptors. Following ligand binding, homo- or heterodimerization occurs and leads to the activation of intrinsic or extrinsic tyrosine kinases, resulting in signal transduction.

Mutations of various CSF receptors have been described which may have clinical sequelae. For example, deletion at the C-terminal end of the cytoplasmic domain of the erythropoietin receptor leads to the development of familial erythrocytosis in humans. Mutations of the gene encoding the thrombopoietin receptor have been identified in all patients with congenital amegakaryocytic thrombocytopenia, a rare disorder characterized by severe hypomegakaryocytic thrombocytopenia in infancy, which develops into pancytopenia in later childhood. In the case of congenital neutropenia, for example Kostmann's syndrome, mutations of the G-CSF receptor appears to be acquired in patients and heralds transformation to myelodys-plastic syndrome (MDS)/acute myeloid leukaemia (AML).

Following growth factor binding to its receptor, a number of signal transduction pathways are activated. The first step in these signalling pathways involves the activation of a tyrosine kinase, either the intrinsic tyrosine kinase domain such as in M-CSF and SCF or an extrinsic tyrosine kinase molecule.

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