Introduction to a review series on normal and pathologic erythropoiesis

In Ancient Greek, ερυθρo (erythro) means red, and ποίησις (poiesis) means to make. This is the etymology of “erythropoiesis,” a term that was coined to define the process of red blood cell (RBC) production in the bone marrow. Erythroid progenitors (burst-forming unit, erythroid and colony-forming unit, erythroid) and precursors (erythroblasts) form the erythroid marrow, whereas erythroid marrow and circulating RBCs are the key components of the human erythron (Figure 1).¹ The kidney oxygen-sensing apparatus and the reticuloendothelial system, which phagocytizes senescent RBCs and returns iron to the erythroid marrow, play a crucial role in the regulation of erythropoiesis (Figure 1).

Abnormalities of the human erythron can result in anemia or erythrocytosis. Anemia is much more common: a systematic analysis of global anemia burden from 1990 to 2010 showed an impressive prevalence of ∼33% in 2010.² Although erythrocytosis is less common, it has many causes that range from rare germline mutations in genes of the hypoxia-inducible factor (HIF) pathway to more common acquired conditions.³ The following series of reviews describes the latest advances in our understanding of normal and pathologic erythropoiesis:

• Gregg L. Semenza, “Breakthrough science: hypoxia-inducible factors, oxygen sensing, and disorders of hematopoiesis”

• Alexis L. Caulier and Vijay G. Sankaran, “Molecular and cellular mechanisms that regulate human erythropoiesis”

• Mario Cazzola, “Ineffective erythropoiesis and its treatment”

Gregg Semenza, together with William Kaelin and Peter Ratcliffe, received the Nobel Prize in Physiology or Medicine 2019 for their discoveries of how cells sense and adapt to oxygen availability. In the “Molecular mechanisms of oxygen sensing” section, Semenza analyzes the breakthrough discoveries that, starting with the isolation of human EPO complementary DNA sequences,^4,5 led to the identification and characterization of the HIF pathway.^6,7 He then focuses on rare Mendelian disorders known as familial erythrocytosis that are associated with mutations of genes encoding components of the HIF pathway, including EPO, EPOR, VHL, EGLN1, EGLN2, and EPAS1. In the last part of his article, Semenza asks whether breakthrough science can yield a breakthrough therapy. He first considers 2 HIF prolyl hydroxylase inhibitors, roxadustat and vadadustat, which have demonstrated efficacy as erythropoiesis-stimulating agents in anemic patients with kidney disease.^8-11 Finally, Semenza focuses on the role of HIFs in hematologic malignancies, emphasizing that HIF activity is increased in many of these neoplasms and concluding that there is an urgent need for the development of safe and effective HIF inhibitors.

Caulier and Sankaran examine the different layers of the regulation of erythropoiesis, which range from cytokine signaling mechanisms that enable extrinsic regulation of RBC production to intrinsic transcriptional pathways necessary for effective erythropoiesis. Then, they analyze posttranscriptional processes that are important in the control of RBC production, including the regulation of ribosome levels. Caulier and Sankaran note that although a classical view of erythropoiesis involves differentiation and maturation through distinct stages of erythroid cells, findings of recent studies are consistent with a more continuous model of erythroid differentiation.¹² Finally, in their outlook for the future, the authors illustrate how single-cell resolution studies may refine our knowledge of erythropoiesis and how this process is perturbed in disease. Hopefully, studies on these subjects will provide opportunities for novel therapies.

My review on ineffective erythropoiesis is primarily aimed at providing a clear definition of this abnormal process, which is responsible for anemia in both inherited and acquired disorders. Ineffective erythropoiesis is characterized by erythropoietin-driven expansion of early-stage erythroid precursors associated with apoptosis of late-stage precursors. In these anemic conditions, erythropoiesis is expanded in terms of the total number of erythroid cells and erythroid marrow iron uptake, but RBC production is inadequate. Although various mechanisms can lead to intramedullary death of erythroid precursors, their common denominator is that they operate in late-stage erythroblasts; early-stage erythroblasts are spared and can therefore expand under Epo drive. The inherited anemias that result from ineffective erythropoiesis are also defined as iron-loading anemias because of the associated parenchymal iron loading caused by the release of erythroid factors such as erythroferrone that suppress hepcidin production. Treatments that specifically target ineffective erythropoiesis are being developed. Luspatercept has been approved for the treatment of anemia in adult patients with β-thalassemia who require regular RBC transfusions¹³ and for the treatment of transfusion-dependent anemia in patients with myelodysplastic syndrome with ring sideroblasts, most of whom carry a somatic SF3B1 mutation.¹⁴ 

I hope that these articles will help readers of Blood improve their knowledge of normal and pathologic erythropoiesis.