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J Invest Dermatol. 2015 Aug;135(8):2093-2101. doi: 10.1038/jid.2015.114. Epub 2015 Mar 27.

Acute Inhibition of MEK Suppresses Congenital Melanocytic Nevus Syndrome in a Murine Model Driven by Activated NRAS and Wnt Signaling.

Author information

1
Institute of Cancer Sciences, University of Glasgow, Glasgow, UK; Beatson Institute for Cancer Research, Glasgow, UK; Current address: Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
2
Institute of Cancer Sciences, University of Glasgow, Glasgow, UK; Beatson Institute for Cancer Research, Glasgow, UK.
3
Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
4
Genetics and Genomic Medicine, UCL Institute of Child Health, London, UK.
5
Beatson Institute for Cancer Research, Glasgow, UK.
6
GOSgene, UCL Institute of Child Health, London, UK.
7
Institute of Neuroscience and Psychology, University of Glasgow, Glasgow, UK.
8
Department of Veterans Affairs, Vanderbilt University Medical Center, Tennessee Valley Healthcare System, Nashville, Tennessee, USA; Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
9
Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
10
Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
11
Genetics and Genomic Medicine, UCL Institute of Child Health, London, UK; Pediatric Dermatology, Great Ormond St Hospital, London, UK. Electronic address: v.kinsler@ucl.ac.uk.
12
Institute of Cancer Sciences, University of Glasgow, Glasgow, UK; Beatson Institute for Cancer Research, Glasgow, UK. Electronic address: p.adams@beatson.gla.ac.uk.

Abstract

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.

PMID:
25815427
PMCID:
PMC4539947
DOI:
10.1038/jid.2015.114
[Indexed for MEDLINE]
Free PMC Article

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