Hematopoietic Tree

A complex, inter-related, and multistep process called hematopoiesis controls the production and development of specific bone marrow cells from immature precursor cells to functional mature blood cells. The earliest cells are stem cells and are multipotential and able to self-renew. Up to 1011 blood cells are produced in an adult human each day. The proliferation of precursor cells, the commitment to one lineage, the maturation of these cells into mature cells, and the survival of hematopoietic cells require the presence of specific growth factors, which act individually and in various combinations in complex feedback mechanisms. The hematopoietic growth factors (HGFs) stimulate cell division, differentiation, maturation, and survival, convert the dividing cells into a population of terminally differentiated functional cells (Fig. 1), and in some cases also activate their mature functions (1-4). Because the literature concerning every aspect of HGF discovery, cloning, function, and clinical use is burgeoning, in this chapter, we mention only a few of the most significant works and cite general references where possible.

These factors are important for both maintaining the steady state and mediating responses to infection. More than 20 HGFs have been identified. The properties of some are described in Table 1. The structure and function of these growth factors have been characterized and the gene that encodes for each factor identified and cloned. Several HGFs are commercially available as recombinant human forms, and they have utility in

From: Cancer Drug Discovery and Development Hematopoietic Growth Factors in Oncology: Basic Science and Clinical Therapeutics Edited by: G. Morstyn, M. A. Foote, and G. J. Lieschke © Humana Press Inc., Totowa, NJ

Hematopoietic Tree
Fig. 1. Hematopoietic tree. EPO, erythropoietin; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; mGDF, megakaryocyte growth and development factor; SCF, stem cell factor; TPO, thrombopoietin. (Courtesy of Amgen, Thousand Oaks, CA.)

clinical practice. These factors include the recombinant forms of two myeloid hematopoietic growth factors, granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF); erythropoietin (EPO), the red cell factor; stem cell factor (SCF), an early-acting HGF; and thrombopoietin (TPO) and interleukin-11 (IL-11), platelet factors. T lymphocytes, monocytes/macrophages, fibroblasts, and endothelial cells are the important cellular sources of most HGFs, excluding EPO and TPO (5,6). EPO is produced primarily by the adult kidney (7-9), and TPO is produced in the liver and in the kidney (10-12).

G-CSF (recombinant products: filgrastim, lenograstim, pegfilgrastim) maintains neutrophil production during steady-state conditions and increases production of neutrophils during acute situations, such as infections (13). Recombinant human G-CSF (rHuG-CSF) reduces neutrophil maturation time from 5 d to 1 d, leading to the rapid release of mature neutrophils from the bone marrow into the blood (14). rHuG-CSF also increases the circulating half-life of neutrophils and enhances chemotaxis and superoxide production (15). Pegfilgrastim is a sustained-duration formulation of rHuG-CSF that has been developed by covalent attachment of a polyethylene glycol molecule to the filgrastim molecule (16).

GM-CSF (recombinant products: molgramostim, sargramostim) is locally active and remains at the site of infection to recruit and activate neutrophils (13). Like G-CSF,

Table 1

Hematopoietic Growth Factors and Their Activities

Factor

MW (kDa) Abbreviation

Target cell

Actions

Erythropoietin 34-39

Granulocyte colony- 18 stimulating factor

Granulocyte- 14-35 macrophage colony-stimulating factor

Interleukin-3 28

Interleukin-5 40-50

Interleukin-7 25

Interleukin-11 23

Monocyte colony- 40-70 stimulating factor

Thrombopoietin 35

EPO Erythoid progenitors (BFU-E, CFU-E) G-CSF Granulocyte progenitors;

mature neutrophils (G-CFC)

GM-CSF Granulocyte, macrophage progenitors (GM-CFC) eosinophil progenitors IL-3 Multipotential progenitor cells

Increase red blood count Increase ANC

IL-5 Eosinophil progenitor cells

IL-7 Early B and T cells

IL 11 Early hemopoietic progenitors, megakaryocytes

M-CSF Monocyte progenitor cells

TPO Stem cells, megakaryocyte and erythroid progenitors

Increase neutrophil, eosinophil, and monocyte count Increase hematopoietic and lymphoid cells Increase eosinophils

Stimulate B

and T cells Increase platelet count

Increase monocytes; but decrease in platelet count Increase platelet count

Abbreviations: ANC, absolute neutrophil count; BFU-E, blast-forming unit-erythroid; CFU-E, colony-forming unit-erythroid; G-CFC, granulocyte colony-forming cell; GM-CFC, granulocyte-macrophage colony-forming cells.

GM-CSF and rHuGM-CSFs stimulate the proliferation, differentiation, and activation of mature neutrophils and enhance superoxide production, phagocytosis, and intracellular killing (17-19). GM-CSF and rHuGM-CSF, unlike G-CSF, stimulate the proliferation, differentiation, and activation of mature monocytes/macrophages (18).

Erythropoietic factors (recombinant products: epoetin alfa, epoetin beta, darbepoetin alfa) increase red blood cell counts by causing committed erythroid progenitor cells to proliferate and differentiate into normoblasts, nucleated precursors in the erythropoietic lineage (20-22). Tissue hypoxia resulting from anemia induces the kidney to increase its production of EPO by a magnitude of a 100-fold or more. EPO stimulates the production of erythroid precursor cells and therefore increases the red blood cell content and oxygen-carrying capacity of blood. Anemia in patients with cancer can be owing to direct or indirect effects of the malignancy on the marrow, or as a complication of myelotoxic chemotherapy or radiotherapy. The onset is often insidious, and some of the clinical effects of anemia have in the past been wrongly attributed to the underlying malignancy. Darbepoetin alfa is another erythropoietic factor that has an extended half-life owing to its increased number of sialic acid-containing carbohydrate molecules (20-21).

SCF (recombinant product: ancestim) is an early-acting hematopoietic growth factor that stimulates the proliferation of primitive hematopoietic and nonhematopoietic cells (2,23). In vitro, SCF has minimal effect on hematopoietic progenitor cells, but it syner-gistically increases the activity of other HGFs, such as G-CSF, GM-CSF, and EPO. SCF and recombinant human (rHu)SCF stimulate generation of dendritic cells in vitro and mast cells in vivo, and rHuSCF has been used in combination with rHuG-CSF to increase progenitor cell mobilization (24).

Thrombopoietic factors (recombinant products: rHuTPO, pegylated megakaryocyte growth and development factor [PEG-rHuMGDF], and rHuIL-11 [oprelvekin]) stimulate the production of megakaryocyte precursors, megakaryocytes, and platelets (10,25,26). IL-11 has many effects on multiple tissues and can interact with IL-3, TPO, or SCF. Endogeous TPO values are increased in patients with thrombocytopenia; it is very effective at increasing the platelet count. TPO is thought to be the major regulator of platelet production.

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