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首页> 外文期刊>The Journal of investigative dermatology. >Acute Inhibition of MEK Suppresses Congenital Melanocytic Nevus Syndrome in a Murine Model Driven by Activated NRAS and Wnt Signaling
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Acute Inhibition of MEK Suppresses Congenital Melanocytic Nevus Syndrome in a Murine Model Driven by Activated NRAS and Wnt Signaling

机译：MEK的急性抑制抑制激活的NRAS和Wnt信号驱动的小鼠模型中的先天性黑素细胞痣综合征。

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Congenital melanocytic nevus (CMN) syndrome is the association of pigmented melanocytic nevi with extra-cutaneous features, classically melanotic cells within the central nervous system, most frequently caused by a mutation of NRAS codon 61. This condition is currently untreatable and carries a significant risk of melanoma within the skin, brain, or leptomeninges. We have previously proposed a key role for Wnt signaling in the formation of melanocytic nevi, suggesting that activated Wnt signaling may be synergistic with activated NRAS in the pathogenesis of CMN syndrome. Some familial pre-disposition suggests a germ-line contribution to CMN syndrome, as does variability of neurological phenotypes in individuals with similar cutaneous phenotypes. Accordingly, we performed exome sequencing of germ-line DNA from patients with CMN to reveal rare or undescribed Wnt-signaling alterations. A murine model harboring activated NRAS(Q61K) and Wnt signaling in melanocytes exhibited striking features of CMN syndrome, in particular neurological involvement. In the first model of treatment for this condition, these congenital, and previously assumed permanent, features were profoundly suppressed by acute post-natal treatment with a MEK inhibitor. These data suggest that activated NRAS and aberrant Wnt signaling conspire to drive CMN syndrome. Post-natal MEK inhibition is a potential candidate therapy for patients with this debilitating condition.
机译：先天性黑素细胞痣（CMN）综合征是色素性黑素细胞痣与皮肤外特征（典型地是中枢神经系统内的黑素细胞）的关联，最常见是由NRAS密码子61突变引起的。这种情况目前无法治疗，并且存在重大风险皮肤，大脑或软脑膜内的黑色素瘤。我们先前已经提出了Wnt信号在黑素细胞痣形成中的关键作用，这表明活化的Wnt信号可能在CMN综合征的发病机理中与活化的NRAS协同作用。一些家族性倾向表明，生殖系对CMN综合症的贡献，与具有相似皮肤表型的个体的神经表型的变异性一样。因此，我们对来自CMN患者的种系DNA进行了外显子组测序，以揭示罕见或未描述的Wnt信号改变。在黑素细胞中具有激活的NRAS（Q61K）和Wnt信号传导的小鼠模型表现出CMN综合征的显着特征，特别是神经系统受累。在针对这种情况的第一个治疗模型中，这些先天性和先前假定的永久性特征通过用MEK抑制剂进行急性产后治疗而得到了深刻抑制。这些数据表明，激活的NRAS和异常的Wnt信号共同驱动了CMN综合症。对于这种使人衰弱的患者，产后MEK抑制是一种潜在的候选疗法。

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