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

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 sign...

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Autores principales: Pawlikowski, Jeffrey S, Brock, Claire, Chen, Sheau-Chiann, Al-Olabi, Lara, Nixon, Colin, McGregor, Fiona, Paine, Simon, Chanudet, Estelle, Lambie, Wendy, Holmes, William M, Mullin, James M, Richmond, Ann, Wu, Hong, Blyth, Karen, King, Ayala, Kinsler, Veronica A, Adams, Peter D
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4539947/
https://www.ncbi.nlm.nih.gov/pubmed/25815427
http://dx.doi.org/10.1038/jid.2015.114
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author Pawlikowski, Jeffrey S
Brock, Claire
Chen, Sheau-Chiann
Al-Olabi, Lara
Nixon, Colin
McGregor, Fiona
Paine, Simon
Chanudet, Estelle
Lambie, Wendy
Holmes, William M
Mullin, James M
Richmond, Ann
Wu, Hong
Blyth, Karen
King, Ayala
Kinsler, Veronica A
Adams, Peter D
author_facet Pawlikowski, Jeffrey S
Brock, Claire
Chen, Sheau-Chiann
Al-Olabi, Lara
Nixon, Colin
McGregor, Fiona
Paine, Simon
Chanudet, Estelle
Lambie, Wendy
Holmes, William M
Mullin, James M
Richmond, Ann
Wu, Hong
Blyth, Karen
King, Ayala
Kinsler, Veronica A
Adams, Peter D
author_sort Pawlikowski, Jeffrey S
collection PubMed
description 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.
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spelling pubmed-45399472015-10-02 Acute Inhibition of MEK Suppresses Congenital Melanocytic Nevus Syndrome in a Murine Model Driven by Activated NRAS and Wnt Signaling Pawlikowski, Jeffrey S Brock, Claire Chen, Sheau-Chiann Al-Olabi, Lara Nixon, Colin McGregor, Fiona Paine, Simon Chanudet, Estelle Lambie, Wendy Holmes, William M Mullin, James M Richmond, Ann Wu, Hong Blyth, Karen King, Ayala Kinsler, Veronica A Adams, Peter D J Invest Dermatol Original Article 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. Nature Publishing Group 2015-08 2015-05-14 /pmc/articles/PMC4539947/ /pubmed/25815427 http://dx.doi.org/10.1038/jid.2015.114 Text en Copyright © 2015 The Society for Investigative Dermatology, Inc http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/
spellingShingle Original Article
Pawlikowski, Jeffrey S
Brock, Claire
Chen, Sheau-Chiann
Al-Olabi, Lara
Nixon, Colin
McGregor, Fiona
Paine, Simon
Chanudet, Estelle
Lambie, Wendy
Holmes, William M
Mullin, James M
Richmond, Ann
Wu, Hong
Blyth, Karen
King, Ayala
Kinsler, Veronica A
Adams, Peter D
Acute Inhibition of MEK Suppresses Congenital Melanocytic Nevus Syndrome in a Murine Model Driven by Activated NRAS and Wnt Signaling
title Acute Inhibition of MEK Suppresses Congenital Melanocytic Nevus Syndrome in a Murine Model Driven by Activated NRAS and Wnt Signaling
title_full Acute Inhibition of MEK Suppresses Congenital Melanocytic Nevus Syndrome in a Murine Model Driven by Activated NRAS and Wnt Signaling
title_fullStr Acute Inhibition of MEK Suppresses Congenital Melanocytic Nevus Syndrome in a Murine Model Driven by Activated NRAS and Wnt Signaling
title_full_unstemmed Acute Inhibition of MEK Suppresses Congenital Melanocytic Nevus Syndrome in a Murine Model Driven by Activated NRAS and Wnt Signaling
title_short Acute Inhibition of MEK Suppresses Congenital Melanocytic Nevus Syndrome in a Murine Model Driven by Activated NRAS and Wnt Signaling
title_sort acute inhibition of mek suppresses congenital melanocytic nevus syndrome in a murine model driven by activated nras and wnt signaling
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4539947/
https://www.ncbi.nlm.nih.gov/pubmed/25815427
http://dx.doi.org/10.1038/jid.2015.114
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