Haematopoietic Growth Factors

Abstract

Haematopoietic growth factors (HGFs) regulate the production of all the cellular elements of blood by stimulating the proliferation, survival and differentiation of haematopoietic cells in various stages of maturation and also enhancing mature cell functions. Certain factors are critical for haematopoiesis in normal health (erythropoietin, thrombopoietin, granulocyte colony‐stimulating factor, macrophage colony‐stimulating factor, interleukin‐7 and stem cell factor) while other growth factors (interleukin‐3, interleukin‐5, interleukin‐6, interleukin‐11 and granulocyte–macrophage colony‐stimulating factor) exert their effects principally in inflammatory states as a response to infection or trauma. Similar to immune cytokines, many HGFs exhibit overlapping roles (redundancy) and dramatic synergy when acting in combination. HGFs transduce their potent biological effects through growth factor receptors which bind HGFs with high affinity and signal through JAK family tyrosine kinases. Recombinant HGFs are used in a wide variety of clinical settings including the treatment for anaemia in kidney disease (erythropoietin), chemotherapy‐induced neutropenia (granulocyte colony‐stimulating factor) and immune‐mediated thrombocytopenia (thrombopoietin) and to aid in the collection of bone marrow stem cells (G‐CSF).

Key Concepts

  • Haematopoietic growth factors (HGFs) are small, secreted extracellular glycoproteins that bind to receptors on the surface of haematopoietic cells
  • Growth factors that are critical for maintenance of blood cell production in normal health are erythropoietin, thrombopoietin, granulocyte colony‐stimulating factor, macrophage colony‐stimulating factor, interleukin‐7 and stem cell factor
  • Interleukin‐3, interleukin‐5, interleukin‐6, interleukin‐11 and granulocyte–macrophage colony‐stimulating factor exert their effects principally in inflammatory states as a response to infection or trauma
  • HGFs are heavily glycosylated proteins that adopt an antiparallel 4‐α helical bundle structure
  • Clinical uses of HGFs continue to increase and include anaemia of renal disease, chemotherapy‐ and drug‐induced neutropenia‐, immune‐mediated thrombocytopenia, aplastic anaemia and anti‐tumour vaccination therapies
  • HGFs exert their effects through specific binding to unique or shared receptor subunits
  • In the case of heterodimeric receptors, the initial sequence of events involves the binding of cytokine to the major binding subunit of the receptor, the alpha subunit, followed by recruitment of the signalling subunit which then undergoes further oligomerisation to bring together two JAK‐2 molecules

Keywords: cytokine; haematopoiesis; receptor; colony‐stimulating factor; signal transduction

Figure 1. (a) Crystal structure of interleukin 3 (Feng, ), an example of a 4‐α helical cytokine with short chains. (b) Crystal structure of interleukin 6 (Somers ., ), a long‐chain 4‐α helical cytokine.
Figure 2. Schematic representation of oligomerisation and high‐order receptor assembly of the βc family of HGF receptors.
Figure 3. Signal transduction pathways for granulocyte–macrophage colony‐stimulating factor (GM‐CSF). Signalling occurs after receptor oligomerisation (βc and GMRα subunits) in the presence of GM‐CSF. Kinases such as JAK2 are activated and phosphorylate tyrosine (Y) residues present on the receptor cytoplasmic tail and other signalling molecules (STAT, SHIP (Src homology 2‐containing inositol phosphatase), Shc and SHP‐2 (Src homology 2‐containing phosphatase)). This leads to activation of ras and contributes to cell proliferation via Raf−1 and MAPK (mitogen‐activated protein kinase). Cell survival is mediated in part by activation of PI3 kinase and the serine kinase Akt. The pathways responsible for differentiation are largely unknown. Other cytokines which use class I haematopoietic receptors have similar signalling mechanisms.
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References

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Further Reading

Hercus TR , Thomas D , Guthridge MA , et al. (2009) The GM‐CSF receptor: linking its structure to cell signalling and its role in disease. Blood 114: 1289–1298.

Heuser M , Ganser A and Bokemeyer C (2007) Use of colony‐stimulating factors for chemotherapy‐associated neutropenia: review of current guidelines. Seminars in Hematology 44: 148–156.

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Nicola NA (ed) (1994) Guidebook to Cytokines and Their Receptors. Oxford: Oxford University Press.

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Thomas, Daniel, and Lopez, Angel F(Jul 2015) Haematopoietic Growth Factors. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001287.pub3]