文章：

来自RASopathies患儿的外周血细胞在体外表现出增强的自发集落形成能力和过度活跃的RAS信号传导

Peripheral blood cells from children with RASopathies show enhanced spontaneous colonies growth in vitro and hyperactive RAS signaling

原文发布日期：2015-07-17

DOI: 10.1038/bcj.2015.52

类型: Original Article

开放获取: 是

英文摘要：

Germline mutations in genes coding for molecules involved in the RAS/RAF/MEK/ERK pathway are the hallmarks of a newly classified family of autosomal dominant syndromes termed RASopathies. Myeloproliferative disorders (MPDs), in particular, juvenile myelomonocytic leukemia, can lead to potentially severe complications in children with Noonan syndrome (NS). We studied 27 children with NS or other RASopathies and 35 age-matched children as control subjects. Peripheral blood (PB) cells from these patients were studied for in vitro colony-forming units (CFUs) activity, as well as for intracellular phosphosignaling. Higher spontaneous growth of both burst-forming units-erythroid (BFU-E) and CFU-granulocyte/macrophage (CFU-GM) colonies from RAS-mutated patients were observed as compared with control subjects. We also observed a significantly higher amount of GM-colony-stimulating factor-induced p-ERK in children with RASopathies. Our findings demonstrate for the first time that PB cells isolated from children suffering from NS or other RASopathies without MPD display enhanced BFU-E and CFU-GM colony formation in vitro. The biological significance of these findings clearly awaits further studies. Collectively, our data provide a basis for further investigating of only partially characterized hematological alterations present in children suffering from RASopathies, and may provide new markers for progression toward malignant MPD in these patients.

摘要翻译： 

编码RAS/RAF/MEK/ERK通路相关分子的基因发生种系突变，是新命名的常染色体显性遗传综合征家族——RASopathies的标志特征。尤其值得注意的是，骨髓增生性疾病（MPDs），特别是幼年型粒单核细胞白血病，可能导致努南综合征（NS）患儿出现潜在严重并发症。我们研究了27名患有NS或其他RASopathies的儿童，并以35名年龄匹配的儿童作为对照对象。对这些患者的外周血（PB）细胞进行了体外集落形成单位（CFUs）活性及细胞内磷酸化信号传导研究。与对照组相比，观察到RAS突变患者红细胞爆裂式形成单位（BFU-E）和粒细胞/巨噬细胞集落形成单位（CFU-GM）的自发性生长增强。同时发现RASopathies患儿中GM-集落刺激因子诱导的p-ERK含量显著升高。我们的研究首次证明，从无MPD的NS或其他RASopathies患儿分离的外周血细胞在体外表现出增强的BFU-E和CFU-GM集落形成能力。这些发现的生物学意义显然有待进一步研究。总体而言，我们的数据为进一步研究RASopathies患儿中仅部分表征的血液学改变提供了基础，并可能为这些患者向恶性MPD进展提供新的标志物。

原文链接：

Peripheral blood cells from children with RASopathies show enhanced spontaneous colonies growth in vitro and hyperactive RAS signaling