铁超载在获得性铁母细胞贫血和MDS:病理生理和作用的螯合和luspaterept。

IF 2.9 3区 教育学 Q1 EDUCATION, SCIENTIFIC DISCIPLINES Hematology. American Society of Hematology. Education Program Pub Date : 2024-12-06 DOI:10.1182/hematology.2024000569
Norbert Gattermann
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引用次数: 0

摘要

除输血治疗外,红细胞生成功能低下还会通过红铁素诱导的肝内hepcidin合成抑制,导致环sideroblasts (MDS-RS)骨髓增生异常综合征的系统性铁超载,导致肠道铁吸收增加。MDS-RS以血红素合成紊乱和线粒体铁积累为特征的潜在病理生理机制尚不清楚。几条线索的证据表明,线粒体转运体ABCB7是关键参与。由于剪接因子SF3B1的体细胞突变,ABCB7在MDS-RS中错误剪接和低表达。ABCB7的致病意义似乎与其稳定铁螯合酶的作用有关,铁螯合酶是一种将铁结合到原卟啉IX中产生血红素的酶。虽然铁相关的氧化应激是有毒的,但许多MDS患者寿命不够长,导致铁超载的临床并发症。此外,很难确定铁超载在多大程度上导致老年MDS患者的发病率和死亡率,因为铁相关并发症与年龄相关的医疗问题重叠。然而,高质量的注册研究表明,输血依赖与有毒铁物种的存在和较差的生存率有关,并证实了铁螯合治疗的显着生存益处。在MDS患者中最广泛使用的铁螯合剂是去铁胺醇,因为它有效且口服方便。Luspatercept可以减少SMAD2/ smad3依赖性信号,这与抑制红细胞生成有关,可能在一年多的时间内消除MDS-RS患者对红细胞输血的需要,从而减少进一步的铁负荷。然而,luspatercept不能指望大大减少现有的铁过载。
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Iron overload in acquired sideroblastic anemias and MDS: pathophysiology and role of chelation and luspatercept.

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.

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来源期刊
Hematology. American Society of Hematology. Education Program
Hematology. American Society of Hematology. Education Program EDUCATION, SCIENTIFIC DISCIPLINES-HEMATOLOGY
CiteScore
4.70
自引率
3.30%
发文量
0
期刊介绍: Hematology, the ASH Education Program, is published annually by the American Society of Hematology (ASH) in one volume per year.
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