Université de Paris, Paris 75006, France.
Institut Cochin, Département Développement, Reproduction, Cancer, Paris 75014, France.
Sci Transl Med. 2019 Jul 10;11(500). doi: 10.1126/scitranslmed.aav5467.
Myelodysplastic syndromes (MDS) with ring sideroblasts are hematopoietic stem cell disorders with erythroid dysplasia and mutations in the splicing factor gene. Patients with MDS with 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 transcript in patients with MDS with the mutation. Induction of this transcript in primary -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 gene mutation than in patients with wild-type MDS. Thus, hepcidin suppression by a variant ERFE is likely responsible for the increased iron loading in patients with -mutated MDS, suggesting that ERFE could be targeted to prevent iron-mediated toxicity. The expression of the variant transcript that was restricted to -mutated erythroblasts decreased in lenalidomide-responsive anemic patients, identifying variant ERFE as a specific biomarker of clonal erythropoiesis.
环形铁幼粒细胞性难治性贫血伴多系发育异常（MDS）是一种造血干细胞疾病，伴有红系发育异常和剪接因子基因突变。携带 MDS 基因突变的患者常伴有组织铁过度积累，即使没有输血也会发生这种情况，但导致实质铁过载的机制尚不清楚。机体铁含量、组织分布以及铁在红细胞生成中的供应均由激素铁调素（hepcidin）控制，铁调素通过红细胞生成素（erythroferrone，ERFE）的分泌由成红细胞进行调节。在这里，我们在携带 基因突变的 MDS 患者中鉴定出一种 转录本。在原发性 -突变骨髓红系细胞中诱导这种 转录本可产生一种变异蛋白，该蛋白仍具有抑制铁调素转录的能力。携带 基因突变的 MDS 患者的 ERFE 血浆浓度高于 野生型 MDS 患者。因此，由变异 ERFE 引起的铁调素抑制可能是导致 -突变 MDS 患者铁过载增加的原因，提示 ERFE 可作为预防铁介导毒性的靶点。局限于 -突变红细胞的变异 转录本的表达在来那度胺反应性贫血患者中减少，这表明变异 ERFE 是克隆性红细胞生成的特异性生物标志物。
