A variant erythroferrone disrupts iron homeostasis in SF3B1-mutated myelodysplastic syndrome
A variant erythroferrone disrupts iron homeostasis in SF3B1-mutated myelodysplastic syndrome
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DOI：
10.1126/scitranslmed.aav5467
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发表时间：
2019-07-10
影响因子：
17.1
通讯作者：
Fontenay, Michaela
中科院分区：
文献类型：
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作者：
Bondu, Sabrina;Alary, Anne-Sophie;Fontenay, Michaela
骨髓增生异常综合征（MDS）伴环形铁粒幼细胞是一种造血干细胞疾病，伴有红系发育异常和SF3B1剪接因子基因突变。具有SF3B1突变的MDS患者即使在没有输血的情况下也经常积累过量的组织铁，但导致其实质铁过载的机制尚不清楚。身体铁含量、组织分布和红细胞生成的铁供应由激素铁调素控制，其由成红细胞通过分泌红系激素erythroferrone（ERFE）调节。在这里，我们确定了一个替代ERFE转录与SF3B1突变的MDS患者。在初级SF3B1突变的骨髓成红细胞中诱导ERFE转录产生了一种变体蛋白，该蛋白保持了抑制铁调素转录的能力。具有SF3B1基因突变的MDS患者的ERFE血浆浓度高于SF3B1野生型MDS患者。因此，铁调素抑制的变体ERFE可能是负责与SF3B1突变的MDS患者的铁负荷增加，这表明ERFE可以有针对性地防止铁介导的毒性。在来那度胺反应性贫血患者中，仅限于SF3B1突变成红细胞的变异ERFE转录物的表达降低，将变异ERFE鉴定为克隆性红细胞生成的特异性生物标志物。
Myelodysplastic syndromes (MDS) with ring sideroblasts are hematopoietic stem cell disorders with erythroid dysplasia and mutations in the SF3B1 splicing factor gene. Patients with MDS with SF3B1 mutations often accumulate excessive tissue iron, even in the absence of transfusions, but the mechanisms that are responsible for their parenchymal iron overload are unknown. Body iron content, tissue distribution, and the supply of iron for erythropoiesis are controlled by the hormone hepcidin, which is regulated by erythroblasts through secretion of the erythroid hormone erythroferrone (ERFE). Here, we identified an alternative ERFE transcript in patients with MDS with the SF3B1 mutation. Induction of this ERFE transcript in primary SF3B1-mutated bone marrow erythroblasts generated a variant protein that maintained the capacity to suppress hepcidin transcription. Plasma concentrations of ERFE were higher in patients with MDS with an SF3B1 gene mutation than in patients with SF3B1 wild-type MDS. Thus, hepcidin suppression by a variant ERFE is likely responsible for the increased iron loading in patients with SF3B1-mutated MDS, suggesting that ERFE could be targeted to prevent iron-mediated toxicity. The expression of the variant ERFE transcript that was restricted to SF3B1-mutated erythroblasts decreased in lenalidomide-responsive anemic patients, identifying variant ERFE as a specific biomarker of clonal erythropoiesis.