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P. Valent et al.
Introduction
Erythropoiesis is one of the important physiological supply functions of the bone marrow. In healthy adults, about 200x109 red cells are produced per day in the bone marrow and are released into the peripheral blood.1 Depending on demand, red cell production can be adjust- ed and upregulated substantially. A complex network of oxygen sensors, cytokines, such as erythropoietin, and other factors, including regulators of iron metabolism, are involved in the control of steady-state and stress-induced erythropoiesis, thereby ensuring appropriate oxygen sup- ply to the peripheral tissues.2-5 This regulatory network can adjust itself to physiological requirements such as the oxygen concentration (altitude) or pregnancy as well as to pathological conditions such as blood loss.2-5 However, in some pathological conditions this regulatory network is overwhelmed or is not functional, resulting in poly- cythemia or anemia.
In the elderly, the bone marrow and other organs under- go aging. As a result, erythropoietin synthesis and red cell production may decline.6-9 However, even in very old indi- viduals, red cell production and erythropoietin synthesis are usually adequate to keep hemoglobin levels within a reasonable range unless certain co-morbidities that lead to insufficient production of red cells have been acquired.6-9 Therefore, such other etiologies must be ruled out when hemoglobin levels drop in older individuals.7-9
Anemia is a major cause of symptomatic morbidity in daily medical practice. The etiologies contributing to ane- mic states are complex.6-14 Underlying disorders include trauma or coagulopathies with consequent bleeding, immunological and other inflammatory reactions as well as clonal (neoplastic) conditions. Clonal expansion of ery- throid progenitor cells in the bone marrow may result in central and peripheral expansion of erythropoiesis, and thus in the clinical picture of polycythemia vera (PV), but it may also result in clonal anemic states such as the myelodysplastic syndromes (MDS) or even erythroid leukemia, characterized by a major or complete block of differentiation in early erythropoiesis.15-18 Anemic MDS are characterized by red cell dysplasia, ineffective erythro- poiesis, apoptosis of late erythroid precursor cells, and the paradoxical combination of erythroid bone marrow hyperplasia and peripheral anemia.
Although several mechanisms underlying normal and pathological red cell production in the bone marrow have been identified in recent years, little is known about dis- ease-related markers and targets through which prognos- tication and therapy may be improved in anemic or poly- cythemic patients. In order to discuss novel markers, tar- gets and mechanisms as well as new therapeutic approaches and strategies in various erythroid disorders, a workshop was organized in Vienna in April 2017 (April 28-29). The discussion in this meeting focused on patho- logical (neoplastic) erythropoiesis in adults. The outcomes of this workshop are summarized in this review.
Erythropoiesis
Molecular mechanisms controlling erythropoiesis in health and disease
A network of interconnected physiological communica- tion networks and pathways are responsible for the pro-
duction, distribution and turnover of red blood cells in healthy individuals (Figure 1).2-5,19-26 These networks keep the hemoglobin concentrations at a remarkably stable level throughout lifetime. Erythropoiesis starts in the bone marrow with lineage commitment of pluripotent myeloid progenitor cells and differentiation of these cells into immature erythroid progenitors that retain a certain pro- liferative capacity. Subsequently, these progenitor cells undergo further differentiation and maturation. A com- plex network of transcription factors and epigenetic regu- lators orchestrates this process.22-31 GATA-1 is the main regulator of lineage commitment, differentiation and sur- vival of erythroid progenitors (Figure 1).20,22,27-30 In particu- lar, GATA-1 triggers erythropoiesis by regulating the tran- scription of several erythroid differentiation-related genes, including genes involved in heme and/or globin synthesis, glycophorins, anti-apoptotic genes of the BH-3 family, genes involved in cell cycle regulation, and the gene for the erythropoietin receptor (EPOR).20,22,28 Major molecular players in these networks include, among others, classical hormones (thyroid hormones, androgens, corticosteroids, activin/inhibin and others), vitamins (e.g. vitamin B12 and folic acid), iron, regulators of iron metabolism such as the transferrin receptors-1 and -2, and early acting hematopoi- etic growth factors such as stem cell factor and inter- leukin-3 (Figure 1A).20-33
The main cytokine regulator of red cell production is erythropoietin, which acts at the level of late erythroid progenitors through a homodimeric receptor that triggers JAK2 kinase activity and subsequently STAT5 activation (Online Supplementary Figure S1). Erythropoietin acts main- ly on myeloid precursor cells to ensure survival, thereby allowing the erythroid differentiation program, induced mainly by GATA-1, to occur (Figure 1A).2-5 It has been sug- gested that erythroid precursors in the bone marrow exhibit differential sensitivity against erythropoietin. The less sensitive cells undergo apoptosis upon caspase activa- tion when the erythropoietin level is low, whereas at higher erythropoietin levels, most cells will survive and differentiate (Figure 1). In addition, in the bone marrow, within erythroid blood islands, late erythroid precursor cells express FAS ligand which may interact with early erythroid precursors that express FAS, resulting in caspase activation, which in turn triggers apoptosis and matura- tion arrest (Figure 1). In the case of a substantial need to produce more erythroid cells (e.g. after blood loss by bleeding or hemolysis), erythropoietin counteracts this activation allowing the cells to survive and differentiate, even if late erythroid precursors are abundant. In erythro- poiesis, caspases, upon activation, cleave not only their main natural targets in the nucleus, but also GATA-1, which amplifies cell death and blocks erythroid differenti- ation (Figure 1).30 Erythropoietin synthesis is regulated in peritubular cells of the kidney by the transcription factor hypoxia-inducible factor-α, the main regulator of tran- scription of the gene encoding for erythropoietin (EPO). The stability of hypoxia-inducible factor-α depends on the prolyl-hydroxylase enzyme and the concentration of oxy- gen.32 To ensure a high level of proliferation and hemoglo- bin synthesis, iron absorption and the availability of iron for erythroid cells are tightly regulated by a number of modulators of iron metabolism and iron uptake. The latter include transferrin and its receptors (TfR-1 and TfR-2), as well as hepcidin and its target ferroportin, which allow iron export from various cell types, including
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haematologica | 2018; 103(10)