PMID- 28548933
OWN - NLM
STAT- MEDLINE
DCOM- 20180423
LR  - 20221207
IS  - 1949-2553 (Electronic)
IS  - 1949-2553 (Linking)
VI  - 8
IP  - 29
DP  - 2017 Jul 18
TI  - KIR2DL5 mutation and loss underlies sporadic dermal neurofibroma pathogenesis and 
      growth.
PG  - 47574-47585
LID - 10.18632/oncotarget.17736 [doi]
AB  - 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 PDGFRbeta and 
      downstream RAS/AKT/mTOR hyperactivation. Importantly, inhibition of PDGFRbeta 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.
FAU - Anastasaki, Corina
AU  - Anastasaki C
AD  - Department of Neurology, Washington University School of Medicine, St. Louis, MO 
      63110, USA.
FAU - Dahiya, Sonika
AU  - Dahiya S
AD  - Department of Pathology, Washington University School of Medicine, St. Louis, MO 
      63110, USA.
FAU - Gutmann, David H
AU  - Gutmann DH
AD  - Department of Neurology, Washington University School of Medicine, St. Louis, MO 
      63110, USA.
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Oncotarget
JT  - Oncotarget
JID - 101532965
RN  - 0 (Receptors, KIR2DL5)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.6.5.2 (ras Proteins)
SB  - IM
MH  - Cell Proliferation
MH  - DNA Mutational Analysis
MH  - Female
MH  - Genes, Neurofibromatosis 1
MH  - *Genetic Association Studies
MH  - *Genetic Predisposition to Disease
MH  - Humans
MH  - Immunohistochemistry
MH  - Male
MH  - *Mutation
MH  - Neurofibroma/*genetics/metabolism/*pathology
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Receptors, KIR2DL5/*genetics
MH  - Schwann Cells/metabolism/pathology
MH  - Signal Transduction
MH  - Skin Neoplasms/*genetics/metabolism/*pathology
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Exome Sequencing
MH  - ras Proteins/metabolism
PMC - PMC5564588
OTO - NOTNLM
OT  - KIR2DL5
OT  - RAS/AKT/mTOR signaling
OT  - Schwann cells
OT  - sporadic neurofibroma
OT  - tumor suppressor gene
COIS- CONFLICTS OF INTEREST The authors declare no competing financial interests.
EDAT- 2017/05/27 06:00
MHDA- 2018/04/24 06:00
PMCR- 2017/07/18
CRDT- 2017/05/27 06:00
PHST- 2016/12/28 00:00 [received]
PHST- 2017/04/24 00:00 [accepted]
PHST- 2017/05/27 06:00 [pubmed]
PHST- 2018/04/24 06:00 [medline]
PHST- 2017/05/27 06:00 [entrez]
PHST- 2017/07/18 00:00 [pmc-release]
AID - 17736 [pii]
AID - 10.18632/oncotarget.17736 [doi]
PST - ppublish
SO  - Oncotarget. 2017 Jul 18;8(29):47574-47585. doi: 10.18632/oncotarget.17736.