Impact of iron overload and potential benefit from iron chelation in low-risk myelodysplastic syndrome

Abstract

Myelodysplastic syndromes (MDSs) are a group of heterogeneous clonal bone marrow disorders characterized by ineffective hematopoiesis, peripheral blood cytopenias, and potential for malignant transformation. Lower/intermediate-risk MDSs are associated with longer survival and high red blood cell (RBC) transfusion requirements resulting in secondary iron overload. Recent data suggest that markers of iron overload portend a relatively poor prognosis, and retrospective analysis demonstrates that iron chelation therapy is associated with prolonged survival in transfusion-dependent MDS patients. New data provide concrete evidence of iron's adverse effects on erythroid precursors in vitro and in vivo. Renewed interest in the iron field was heralded by the discovery of hepcidin, the main serum peptide hormone negative regulator of body iron. Evidence from β-thalassemia suggests that regulation of hepcidin by erythropoiesis dominates regulation by iron. Because iron overload develops in some MDS patients who do not require RBC transfusions, the suppressive effect of ineffective erythropoiesis on hepcidin may also play a role in iron overload. We anticipate that additional novel tools for measuring iron overload and a molecular-mechanism-driven description of MDS subtypes will provide a deeper understanding of how iron metabolism and erythropoiesis intersect in MDSs and improve clinical management of this patient population.

Figure 1

Hepcidin regulation by erythropoiesis and its effects on iron efflux from cells involved in iron metabolism. Hepcidin plays a central role in the maintenance of iron homeostasis and regulation of plasma iron concentrations by controlling ferroportin concentrations on iron-exporting cells, including duodenal enterocytes, recycling macrophages of the spleen and liver, and hepatocytes (involved in iron storage). The bone marrow has the highest iron requirements for hemoglobin synthesis, and thus, increased erythropoietic activity suppresses hepcidin production. Several potential candidate erythroid regulators of hepcidin (eg, GDF15 and TWSG1) in β-thalassemia have been reported. Recently, a non–disease-specific mechanism has been proposed (eg, ERFE). EPO, erythropoietin; Fe, iron; TWSG1, twisted gastrulation 1.

Figure 2

Model effect of erythropoiesis on hepcidin expression between RBC's transfusions. Ultimate hepcidin concentrations are the sum of effects from multiple regulators. RBC transfusions both suppress endogenous erythropoiesis and ultimately result in the accumulation of iron, released from transfused RBCs at the end of their life cycle. Thus, hepcidin is initially derepressed after RBC transfusion and progressively decreases to pretransfusion levels, mirroring hemoglobin and endogenous erythropoietin concentrations (modified from data in Ghoti et al). epo, erythropoietin; Hb, hemoglobin; TX, transfusion.

Figure 3

Model of crosstalk between erythropoiesis and iron metabolism involving TGF-β family member GDF11. Erythroid precursor proliferation and differentiation is regulated in part by multiple members of the TGF-β family. GDF11 binding to ActRII results in Smad2,3 phosphorylation and leads to the expansion of erythroid precursors and suppresses differentiation, resulting in ineffective erythropoiesis and iron overload. Hepcidin expression in hepatocytes is stimulated through the iron pathway (through bone morphogenic protein receptor signaling and Smad1,5,8 phosphorylation) and suppressed through the erythropoiesis pathway (possibly through ERFE binding and signaling through a yet-unidentified receptor). ActRII, activin receptor IIa; BMP6, bone morphogenic protein 6; BMPR, bone morphogenic protein receptor; GDF11, growth differentiation factor 11; R-Smad, receptor-mediated decapentaplegic protein; R-Smad-P, phosphorylated R-Smad.