Iron overload in acquired sideroblastic anemias and MDS: pathophysiology and role of chelation and luspatercept.
| Autor: | Gattermann N; Heinrich Heine University Düsseldorf, Düsseldorf, Germany. |
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| Jazyk: | angličtina |
| Zdroj: | Hematology. American Society of Hematology. Education Program [Hematology Am Soc Hematol Educ Program] 2024 Dec 06; Vol. 2024 (1), pp. 443-449. |
| DOI: | 10.1182/hematology.2024000569 |
| Abstrakt: | Besides transfusion therapy, ineffective erythropoiesis contributes to systemic iron overload in myelodysplastic syndromes with ring sideroblasts (MDS-RS) via erythroferrone-induced suppression of hepcidin synthesis in the liver, leading to increased intestinal iron absorption. The underlying pathophysiology of MDS-RS, characterized by disturbed heme synthesis and mitochondrial iron accumulation, is less well understood. Several lines of evidence indicate that the mitochondrial transporter ABCB7 is critically involved. ABCB7 is misspliced and underexpressed in MDS-RS, due to somatic mutations in the splicing factor SF3B1. The pathogenetic significance of ABCB7 seems related to its role in stabilizing ferrochelatase, the enzyme incorporating iron into protoporphyrin IX to make heme. Although iron-related oxidative stress is toxic, many patients with MDS do not live long enough to develop clinical complications of iron overload. Furthermore, it is difficult to determine the extent to which iron overload contributes to morbidity and mortality in older patients with MDS, because iron-related complications overlap with age-related medical problems. Nevertheless, high-quality registry studies showed that transfusion dependency is associated with the presence of toxic iron species and inferior survival and confirmed a significant survival benefit of iron chelation therapy. The most widely used iron chelator in patients with MDS is deferasirox, owing to its effectiveness and convenient oral administration. Luspatercept, which can reduce SMAD2/SMAD3-dependent signaling implicated in suppression of erythropoiesis, may obviate the need for red blood cell transfusion in MDS-RS for more than a year, thereby diminishing further iron loading. However, luspatercept cannot be expected to substantially reduce the existing iron overload. (Copyright © 2024 by The American Society of Hematology.) |
| Databáze: | MEDLINE |
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