Acute Inhibition of MEK Suppresses Congenital Melanocytic Nevus Syndrome in a Murine Model Driven by Activated NRAS and Wnt Signaling.
Acute Inhibition of MEK Suppresses Congenital Melanocytic Nevus Syndrome in a Murine Model Driven by Activated NRAS and Wnt Signaling.
复制标题
DOI：
10.1038/jid.2015.114
复制
发表时间：
2015-08
期刊：
影响因子：
--
通讯作者：
Adams PD
中科院分区：
文献类型：
--
作者：
Pawlikowski JS;Brock C;Chen SC;Al-Olabi L;Nixon C;McGregor F;Paine S;Chanudet E;Lambie W;Holmes WM;Mullin JM;Richmond A;Wu H;Blyth K;King A;Kinsler VA;Adams PD
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的关联，典型地是中枢神经系统内的黑素细胞，最常见地由NRAS密码子61的突变引起。这种情况目前无法治疗，并且存在皮肤、大脑或软脑膜内患黑色素瘤的重大风险。我们以前提出了一个关键的作用，Wnt信号在黑素细胞痣的形成，表明激活Wnt信号可能是协同与激活NRAS在CMN综合征的发病机制。一些家族性倾向表明CMN综合征的生殖系贡献，在具有相似皮肤表型的个体中神经表型的变异性也是如此。因此，我们对CMN患者的生殖系DNA进行了外显子组测序，以揭示罕见或未描述的Wnt信号转导改变。在黑素细胞中含有活化的NRASQ61K和Wnt信号传导的鼠模型表现出CMN综合征的显著特征，特别是神经系统受累。在治疗这种疾病的第一个模型中，这些先天性和先前假定的永久性特征被用MEK抑制剂进行的急性产后治疗深刻抑制。这些数据表明，激活的NRAS和异常Wnt信号转导共同驱动CMN综合征。出生后MEK抑制是一种潜在的候选疗法，用于这种衰弱性疾病的患者。
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 NRASQ61K 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.