Controversies on the Consequences of Iron Overload and Chelation in MDS

Abstract

Many patients with MDS are prone to develop systemic and tissue iron overload in part as a consequence of disease-immanent ineffective erythropoiesis. However, chronic red blood cell transfusions, which are part of the supportive care regimen to correct anemia, are the major source of iron overload in MDS. Increased systemic iron levels eventually lead to the saturation of the physiological systemic iron carrier transferrin and the occurrence of non-transferrin-bound iron (NTBI) together with its reactive fraction, the labile plasma iron (LPI). NTBI/LPI-mediated toxicity and tissue iron overload may exert multiple detrimental effects that contribute to the pathogenesis, complications and eventually evolution of MDS. Until recently, the evidence supporting the use of iron chelation in MDS was based on anecdotal reports, uncontrolled clinical trials or prospective registries. Despite not fully conclusive, these and more recent studies, including the TELESTO trial, unravel an overall adverse action of iron overload and therapeutic benefit of chelation, ranging from improved hematological outcome, reduced transfusion dependence and superior survival of iron-loaded MDS patients. The still limited and somehow controversial experimental and clinical data available from preclinical studies and randomized trials highlight the need for further investigation to fully elucidate the mechanisms underlying the pathological impact of iron overload-mediated toxicity as well as the effect of classic and novel iron restriction approaches in MDS. This review aims at providing an overview of the current clinical and translational debated landscape about the consequences of iron overload and chelation in the setting of MDS.

Figure 1

Iron homeostasis and signaling pathways involved in hepcidin regulation. (A) Iron transported in the circulation (3 mg) is mostly used for hemoglobin (Hb) synthesis to support de novo red blood cell (RBC) production. Iron is absorbed daily in small amount by duodenal enterocytes (1–2 mg) to replace ordinary iron losses. Iron supply to the bone marrow is mostly maintained by iron recycling in reticulo-endothelial macrophages (20–25 mg), which engulf senescent RBCs and release iron back into circulation. The liver serves as major iron storage tissue (1 g), where iron accumulates in ferritins in a non-toxic form. Due to the lack of active iron excretion systems, iron absorption and recycling are tightly regulated to maintain iron homeostasis. Hepcidin orchestrates systemic iron fluxes through the iron exporter ferroportin (FPN) by binding it on the surface of iron-releasing cells (macrophages and enterocytes), inducing its degradation and blocking systemic iron release. (B) Hepcidin production in the liver is regulated by multiple and opposing signals. Elevated iron stores and inflammation induce hepcidin in order to prevent iron overload and deprive microrganisms of growth-essential iron, respectively. Whereas BMP2 is more involved in steady-state hepcidin expression, BMP6 production is induced by increased iron levels and triggers hepcidin transcription via the bone morphogenic protein (BMP) / sma and mothers against decapentaplegic homologue (SMAD) pathway. High concentrations of diferric transferrin (Tf-Fe₂) displace HFE from transferrin receptor 1 (TFR1), which then forms a complex with transferrin receptor 2 (TFR2) and hemojuvelin (HJV) to promote BMP/SMAD signaling. HJV contributes to the BMP/SMAD signaling acting as BMP co-receptor and is negatively regulated by Matriptase 2 (TMPRSS6)-mediated cleavage. Under inflammatory conditions, interleukin 6 (IL-6) induces hepcidin mRNA via the Jak/signal transducer and activator of transcription (STAT) pathway. Increased erythropoietic demand and hypoxia suppress hepcidin production, enabling iron supply for erythropoiesis. Hypoxia induces the renal production of erythropoietin (EPO) which is responsible for erythropoiesis stimulation. Increased EPO induces the synthesis of erythroferrone (ERFE) and growth differentiation factor 11(GDF11) by erythroid precursors, resulting in hepcidin suppression. In hepatocytes ERFE and GDF11 interferes with the BMP/SMAD signaling pathway by sequestering BMP6, and by enhancing SMAD ubiquitin regulatory factor 1 (SMURF1) expression, respectively. Other erythropoietic regulators such as growth differentiation factor 15 (GDF-15) and twisted gastrulation factor 1 (TWSG1), have been implicated in hepcidin regulation, though not so definitely. To some extent hypoxia inducible factor (HIF) might be directly implicated in hepcidin downregulation. BMPR-I = Bone Morphogenic Protein Receptor Type 1; BMPR-II = Bone Morphogenic Protein Receptor Type 2; IL6-R = Interleukin-6 Receptor.

Figure 2

Mechanisms and consequences of iron overload in MDS. Ineffective erythropoiesis and chronic transfusions are major causes of iron overload in MDS. Insufficiently elevated hepcidin is implicated as a cause of primary iron overload, leading to inappropriately high iron absorption and recycling. In condition of increased erythropoietic demand, bone marrow ERFE production suppresses hepcidin synthesis via BMP sequestration and interference with the BMP/SMAD pathway in hepatocytes. MDS results in iron overload predominantly from excess iron acquisition through repeated RBC transfusions. Highly elevated systemic iron through increased absorption and recycling causes transferrin saturation and NTBI formation. NTBI eventually accumulates in tissues and promotes organ and cell damage through its pro-oxidant and pro-inflammatory action. Clinical features associated with iron overload in MDS might include hepatic dysfunction, cardiomyopathy, atherosclerosis, bone marrow alterations, leukemic progression, erythropoiesis impairment and predisposition to infections. BM = bone marrow; BMP = bone morphogenetic proteins; ERFE = erythroferrone; NTBI = non-transferrin-bound iron; ROS = reactive oxygen species.