KIR2DL5 mutation and loss underlies sporadic dermal neurofibroma pathogenesis and growth.
Oncotarget
; 8(29): 47574-47585, 2017 Jul 18.
Article
em En
| MEDLINE
| ID: mdl-28548933
ABSTRACT
Dermal neurofibromas (DNFs) are benign peripheral nerve sheath tumors thought to originate from Schwann cell progenitors. These tumors represent one of the hallmarks of the neurofibromatosis type 1 (NF1) tumor predisposition syndrome, where they can number in the thousands. While NF1-DNFs arise due to mutations in the NF1 gene, the vast majority of DNFs occur sporadically (sp-DNFs), where the genetic etiology is currently unknown. Herein, we employed whole-exome sequencing of sp-DNFs to identify a recurrent mutation in the KIR2DL5 gene, which codes for a protein suppressor of natural killer (NK) cell activity. While the function of KIR2DL5 outside of the immune system is unknown, we identified a KIR2DL5N173D mutation in three of nine sp-DNFs, resulting in loss of KIR2DL5 protein expression. In contrast, two of these subjects had unrelated tumors, which retained KIR2DL5 protein expression. Moreover, loss of KIR2DL5 expression was demonstrated in 15 of 45 independently-identified sp-DNFs. Consistent with its potential role as a negative growth regulator important for neurofibroma maintenance, ectopic KIR2DL5N173D expression in normal human Schwann cells resulted in reduced KIR2DL5 expression and increased cell proliferation. Similarly, KIR2DL5 short hairpin RNA knockdown (KD) decreased KIR2DL5 protein levels and increased cell proliferation, as well as correlated with PDGFRß and downstream RAS/AKT/mTOR hyperactivation. Importantly, inhibition of PDGFRß or AKT/mTOR activity in KIR2DL5-KD human Schwann cells reduced proliferation to control levels. Collectively, these findings establish KIR2DL5 as a new Schwann cell growth regulator relevant to sp-DNF pathogenesis, which links sporadic and NF1-associated DNFs through RAS pathway hyperactivation.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Cutâneas
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Predisposição Genética para Doença
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Receptores KIR2DL5
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Estudos de Associação Genética
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Mutação
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Neurofibroma
Tipo de estudo:
Etiology_studies
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Prognostic_studies
Limite:
Female
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Humans
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Male
Idioma:
En
Revista:
Oncotarget
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Estados Unidos