Anemia: progress in molecular mechanisms and therapies

Abstract

Anemia is a major source of morbidity and mortality worldwide. Here we review recent insights into how red blood cells (RBCs) are produced, the pathogenic mechanisms underlying various forms of anemia, and novel therapies derived from these findings. It is likely that these new insights, mainly arising from basic scientific studies, will contribute immensely to both the understanding of frequently debilitating forms of anemia and the ability to treat affected patients. Major worldwide diseases that are likely to benefit from new advances include the hemoglobinopathies (β-thalassemia and sickle cell disease); rare genetic disorders of RBC production; and anemias associated with chronic kidney disease, inflammation, and cancer. Promising new approaches to treatment include drugs that target recently defined pathways in RBC production, iron metabolism, and fetal globin-family gene expression, as well as gene therapies that use improved viral vectors and newly developed genome editing technologies.

Figure 1

A model for hematopoiesis. The long term hematopoietic stem cell (LT-HSC) gives rise to short term hematopoietic stem cells (ST-HSCs) that then give rise to the multipotent common myeloid progenitor (CMP) and common lymphoid progenitor (CLP). The CMP then gives rise to megakaryocyte-erythroid progenitors (MEPs) and granulocyte-macrophage progenitors (GMPs). The maturation of lineage-committed erythroid progenitors is shown on the left side. The earliest progenitor, burst forming unit erythroid (BFU-E), gives rise to the colony forming unit erythroid (CFU-E). These two progenitors are identified by colony assays. The CFU-E differentiates into morphologically distinct precursors that undergo progressive maturation: proerythroblasts (ProE), basophilic erythroblasts (BasoE), polychromatic erythroblasts (PolyE), and orthochromatic erythroblasts (OrthoE). The latter enucleate to produce reticulocytes (Retic) that are released into the circulation and mature further into red blood cells (RBCs).). EPO promotes the survival and proliferation of multiple erythroid progenitors and precursors from late BFU-E to basophilic erythroblast stages.

Figure 2

Stimulatory and inhibitory pathways regulating erythropoiesis. EPO engages EpoR on erythroid precursors to activate a signaling cascade that begins with JAK2, thereby facilitating survival and proliferation. EPO mRNA is normally secreted from a subset of adult kidney cells and its expression is regulated by hypoxia inducible transcription factor (HIF) family members. Hypoxia stabilizes HIF proteins by inhibiting the activity of prolyl hydroxylase enzymes (PHD) that stimulate HIF degradation. Pharmacological prolyl hydroxylase inhibitors (PHI) stabilize HIF to stimulate EPO production, not only in the kidney as shown, but also in the liver of anephric patients (not shown). Growth differentiation factor 11 (GDF11) may negatively regulate erythropoiesis by engaging transforming growth factor β receptors and is blocked by activin receptor traps, including Sotatercept and ACE-536. The physiological source of GDF11 is currently unknown.

Figure 3

Regulation of fetal hemoglobin (HbF) production. (a) Timing of β-like globin subunit switching during human ontogeny. The embryonic, fetal, and adult stages are shown in blue, green, and red, respectively. (b) Regulators of hemoglobin switching including BCL11A, KLF1, MYB, TR2, TR4, LSD1, HDAC1, and HDAC2 as well as their modes of proposed regulation are depicted here. Some factors, including the BCL11A complex repress γ-globin through indirect mechanisms of action and are therefore shown with dotted lines. BCL11A binding sites are indicated with an asterix. Corepressor complexes that associated with BCL11A and other regulators are depicted in red.

Figure 4

Regulation of iron homeostasis. Hepcidin gene transcription in hepatocytes is regulated by BMP6, BMP6 receptors, the co-receptor hemojuvelin (HJV) and inflammatory cytokines such as interleukin 6 (not shown). TMPRSS6 cleaves HJV to inhibit hepcidin production. Secreted hepcidin binds ferroportin and stimulates its degradation, resulting in decreased intestinal iron absorption and iron accumulation in reticuloendothelial cells. During ineffective erythropoiesis in β-thalassemia and other disorders, accumulated bone marrow erythroid precursors release erythroferrone and GDF15, which suppress liver hepcidin production, causing inappropriate iron absorption and release of iron from reticuloendothelial cells.

Figure 5

Gene therapy or editing to treat congenital forms of anemia. Potential corrective approaches for β thalassemia or sickle cell disease are shown. These approaches can also be used to correct various other severe anemias caused by monogenic mutations.