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首页> 外文期刊>International Journal of Molecular Sciences >RAP-011 Rescues the Disease Phenotype in a Cellular Model of Congenital Dyserythropoietic Anemia Type II by Inhibiting the SMAD2-3 Pathway
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RAP-011 Rescues the Disease Phenotype in a Cellular Model of Congenital Dyserythropoietic Anemia Type II by Inhibiting the SMAD2-3 Pathway

机译：RAP-011通过抑制SMAD2-3途径侦察先天性脱胸腔贫血型II型的蜂窝模型中的疾病表型

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Congenital dyserythropoietic anemia type II (CDA II) is a hypo-productive anemia defined by ineffective erythropoiesis through maturation arrest of erythroid precursors. CDA II is an autosomal recessive disorder due to loss-of-function mutations in SEC23B . Currently, management of patients with CDA II is based on transfusions, splenectomy, or hematopoietic stem-cell transplantation. Several studies have highlighted benefits of ACE-011 (sotatercept) treatment of ineffective erythropoiesis, which acts as a ligand trap against growth differentiation factor (GDF)11. Herein, we show that GDF11 levels are increased in CDA II, which suggests sotatercept as a targeted therapy for treatment of these patients. Treatment of stable clones of SEC23B -silenced erythroleukemia K562 cells with the iron-containing porphyrin hemin plus GDF11 increased expression of pSMAD2 and reduced nuclear localization of the transcription factor GATA1, with subsequent reduced gene expression of erythroid differentiation markers. We demonstrate that treatment of these SEC23B -silenced K562 cells with RAP-011, a “murinized” ortholog of sotatercept, rescues the disease phenotype by restoring gene expression of erythroid markers through inhibition of the phosphorylated SMAD2 pathway. Our data also demonstrate the effect of RAP-011 treatment in reducing the expression of erythroferrone in vitro, thus suggesting a possible beneficial role of the use of sotatercept in the management of iron overload in patients with CDA II.
机译：先天性脱疑性贫血II型（CDA II）是一种缺氧贫血，其通过成熟的红细胞前体的成熟捕获而定义。 CDA II是SEC23B中功能突变损失的常染色体隐性障碍。目前，CDA II患者的管理基于输血，脾切除或造血干细胞移植。几项研究突出了ACE-011（SOTatercept）治疗无效促红细胞生成的益处，其作为抗生长分化因子（GDF）11的配体捕集。在此，我们表明CDA II中的GDF11水平增加，这表明SOTATERCOpp作为治疗这些患者的目标治疗。用含铁卟啉血红素加上GDF11对含铁卟啉血红蛋白的稳定克隆的克隆克隆的治疗增加了PSMAD2的表达，降低了转录因子GATA1的核定位，随后降低了红细胞分化标志物的基因表达。我们证明，使用RAP-011对这些SEC23B -SILENCED的K562细胞进行治疗，通过抑制磷酸化SMAD2途径来恢复红细胞标记物的基因表达来拯救疾病表型。我们的数据还证明了RAP-011治疗在体外降低红萜烫伤表达的影响，从而表明使用了机atercept在CDA II患者的铁过载中的管理中可能的有益作用。

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