激活素受体配体陷阱治疗骨髓增生异常综合征疗效的生物学基础
Biological basis for efficacy of activin receptor ligand traps in myelodysplastic syndromes.
作者信息
Verma Amit, Suragani Rajasekhar Nvs, Aluri Srinivas, Shah Nishi, Bhagat Tushar D, Alexander Mark J, Komrokji Rami, Kumar Ravi
机构信息
Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York, USA.
Acceleron Pharma, Cambridge, Massachusetts, USA.
出版信息
J Clin Invest. 2020 Feb 3;130(2):582-589. doi: 10.1172/JCI133678.
Abstract
Signaling by the TGF-β superfamily is important in the regulation of hematopoiesis and is dysregulated in myelodysplastic syndromes (MDSs), contributing to ineffective hematopoiesis and clinical cytopenias. TGF-β, activins, and growth differentiation factors exert inhibitory effects on red cell formation by activating canonical SMAD2/3 pathway signaling. In this Review, we summarize evidence that overactivation of SMAD2/3 signaling pathways in MDSs causes anemia due to impaired erythroid maturation. We also describe the basis for biological activity of activin receptor ligand traps, novel fusion proteins such as luspatercept that are promising as erythroid maturation agents to alleviate anemia and related comorbidities in MDSs and other conditions characterized by impaired erythroid maturation.
摘要
转化生长因子-β（TGF-β）超家族的信号传导在造血调控中起重要作用，并且在骨髓增生异常综合征（MDS）中失调，导致无效造血和临床血细胞减少。TGF-β、激活素和生长分化因子通过激活经典的SMAD2/3信号通路对红细胞生成产生抑制作用。在本综述中，我们总结了证据表明，MDS中SMAD2/3信号通路的过度激活由于红系成熟受损而导致贫血。我们还描述了激活素受体配体陷阱的生物学活性基础，这是一种新型融合蛋白，如罗特西普，有望作为红系成熟剂来缓解MDS和其他以红系成熟受损为特征的疾病中的贫血及相关合并症。
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