Neurofibromin-deficient fibroblasts fail to form perineurium in vitro

Development ◽  
1995 ◽  
Vol 121 (11) ◽  
pp. 3583-3592
Author(s):  
T. Rosenbaum ◽  
Y.L. Boissy ◽  
K. Kombrinck ◽  
C.I. Brannan ◽  
N.A. Jenkins ◽  
...  
Keyword(s):  
Schwann Cells ◽  
Neurofibromatosis Type 1 ◽  
Fibroblast Cell ◽  
Neurofibromatosis Type ◽  
Type I ◽  
Nerve Sheath Tumors ◽  
Cell Strains ◽  
Perineurial Cells

To identify cell type(s) that might contribute to nerve sheath tumors (neurofibromas) in patients with neurofibromatosis type 1, we generated cell cultures containing neurons. Schwann cells and fibroblasts from transgenic mouse embryos in which the type 1 neurofibromatosis gene was disrupted by homologous recombination (Brannan et al. (1994) Genes Development, 8,1019-1029). Normal fascicle formation by perineurial cells failed to occur in the absence of neurofibromin. Fascicles were reduced in number and showed abnormal morphology when normal neurons and Schwann cells were cultured up to 37 days with fibroblasts lacking neurofibromin. Proliferation was increased in a majority of fibroblast cell strains analyzed from embryos lacking neurofibromin. These observations suggest that mutations in the neurofibromatosis type I gene affect fibroblast behavior that might contribute to neurofibroma formation in patients with neurofibromatosis type 1.

The Association of Chiari Type I Malformation and Neurofibromatosis Type 1

1993 ◽  
Vol 32 (3) ◽  
pp. 189-190 ◽  
Author(s):  
Joseph Dooley ◽  
Daniel Vaughan ◽  
Michael Riding ◽  
Peter Camfield
Keyword(s):  
Neurofibromatosis Type 1 ◽  
Chiari Malformation ◽  
Neurofibromatosis Type ◽  
Foramen Magnum ◽  
Type I ◽  
Chiari Type ◽  
Chiari Type I Malformation ◽  
Chiari Type I ◽  
Chiari Malformations

The association of neurofibromatosis type 1 (NF1) with Chiari malformations of the cerebellum and brain stem has been reported on only two previous occasions.1,2 The pathogenesis of both conditions has remained unclear, although the Chiari type I malformation is most likely due to hypoplasia of the posterior fossa with subsequent extension of the cerebellum through the foramen magnum.3 NF1 is also associated with a variety of cerebral dysplasias.4 We present a patient with both of these dysplastic lesions whose Chiari malformation was asymptomatic.

scholarly journals New Model Systems and the Development of Targeted Therapies for the Treatment of Neurofibromatosis Type 1-Associated Malignant Peripheral Nerve Sheath Tumors

Genes ◽  
2020 ◽  
Vol 11 (5) ◽  
pp. 477 ◽  
Author(s):  
Kyle B. Williams ◽  
David A. Largaespada
Keyword(s):  
Schwann Cell ◽  
Peripheral Nerve ◽  
Neurofibromatosis Type 1 ◽  
Single Agent ◽  
Neurofibromatosis Type ◽  
Mek Inhibitors ◽  
Nerve Sheath Tumors ◽  
Peripheral Nerve Sheath Tumors ◽  
Nerve Sheath

Neurofibromatosis Type 1 (NF1) is a common genetic disorder and cancer predisposition syndrome (1:3000 births) caused by mutations in the tumor suppressor gene NF1. NF1 encodes neurofibromin, a negative regulator of the Ras signaling pathway. Individuals with NF1 often develop benign tumors of the peripheral nervous system (neurofibromas), originating from the Schwann cell linage, some of which progress further to malignant peripheral nerve sheath tumors (MPNSTs). Treatment options for neurofibromas and MPNSTs are extremely limited, relying largely on surgical resection and cytotoxic chemotherapy. Identification of novel therapeutic targets in both benign neurofibromas and MPNSTs is critical for improved patient outcomes and quality of life. Recent clinical trials conducted in patients with NF1 for the treatment of symptomatic plexiform neurofibromas using inhibitors of the mitogen-activated protein kinase (MEK) have shown very promising results. However, MEK inhibitors do not work in all patients and have significant side effects. In addition, preliminary evidence suggests single agent use of MEK inhibitors for MPNST treatment will fail. Here, we describe the preclinical efforts that led to the identification of MEK inhibitors as promising therapeutics for the treatment of NF1-related neoplasia and possible reasons they lack single agent efficacy in the treatment of MPNSTs. In addition, we describe work to find targets other than MEK for treatment of MPNST. These have come from studies of RAS biochemistry, in vitro drug screening, forward genetic screens for Schwann cell tumors, and synthetic lethal screens in cells with oncogenic RAS gene mutations. Lastly, we discuss new approaches to exploit drug screening and synthetic lethality with NF1 loss of function mutations in human Schwann cells using CRISPR/Cas9 technology.

scholarly journals MicroRNAome profiling in benign and malignant neurofibromatosis type 1-associated nerve sheath tumors: evidences of PTEN pathway alterations in early NF1 tumorigenesis

BMC Genomics ◽  
2013 ◽  
Vol 14 (1) ◽  
pp. 473 ◽  
Author(s):  
Julien Masliah-Planchon ◽  
Eric Pasmant ◽  
Armelle Luscan ◽  
Ingrid Laurendeau ◽  
Nicolas Ortonne ◽  
...  
Keyword(s):  
Neurofibromatosis Type 1 ◽  
Neurofibromatosis Type ◽  
Nerve Sheath Tumors ◽  
Nerve Sheath

Mutations of the NF1 Gene in Children With Juvenile Myelomonocytic Leukemia Without Clinical Evidence of Neurofibromatosis, Type 1

Blood ◽  
1998 ◽  
Vol 92 (1) ◽  
pp. 267-272 ◽  
Author(s):  
Lucy E. Side ◽  
Peter D. Emanuel ◽  
Brigit Taylor ◽  
Janet Franklin ◽  
Patricia Thompson ◽  
...  
Keyword(s):  
Clinical Diagnosis ◽  
Neurofibromatosis Type 1 ◽  
Neurofibromatosis Type ◽  
Juvenile Myelomonocytic Leukemia ◽  
Translation System ◽  
Polymorphism Analysis ◽  
Single Stranded Conformational Polymorphism ◽  
Myelomonocytic Leukemia

Juvenile myelomonocytic leukemia (JMML) is a pediatric myelodysplastic syndrome that is associated with neurofibromatosis, type 1 (NF1). The NF1 tumor suppressor gene encodes neurofibromin, which regulates the growth of immature myeloid cells by accelerating guanosine triphosphate hydrolysis on Ras proteins. The purpose of this study was to determine if the NF1gene was involved in the pathogenesis of JMML in children without a clinical diagnosis of NF1. An in vitro transcription and translation system was used to screen JMML marrows from 20 children for NF1mutations that resulted in a truncated protein. Single-stranded conformational polymorphism analysis was used to detect RASpoint mutations in these samples. We confirmed mutations of NF1in three leukemias, one of which also showed loss of the normalNF1 allele. An NF1 mutation was detected in normal tissue from the only patient tested and this suggests that JMML may be the presenting feature of NF1 in some children. Activating RASmutations were found in four patients; as expected, none of these samples harbored NF1 mutations. Because 10% to 14% of children with JMML have a clinical diagnosis of NF1, these data are consistent with the existence of NF1 mutations in approximately 30% of JMML cases.

scholarly journals An Imprinted Locus Epistatically Influences Nstr1 and Nstr2 to Control Resistance to Nerve Sheath Tumors in a Neurofibromatosis Type 1 Mouse Model

2006 ◽  
Vol 66 (1) ◽  
pp. 62-68 ◽  
Author(s):  
Karlyne M. Reilly ◽  
Karl W. Broman ◽  
Roderick T. Bronson ◽  
Shirley Tsang ◽  
Dagan A. Loisel ◽  
...  
Keyword(s):  
Mouse Model ◽  
Neurofibromatosis Type 1 ◽  
Neurofibromatosis Type ◽  
Nerve Sheath Tumors ◽  
Nerve Sheath

Serum mitogenic activity on in vitro glial cells in Neurofibromatosis type 1

1998 ◽  
Vol 793 (1-2) ◽  
pp. 21-28 ◽  
Author(s):  
Brunella Caronti ◽  
Francesca Romana Buttarelli ◽  
Sandra Giustini ◽  
Caterina Calderaro ◽  
Luigi Calandriello ◽  
...  
Keyword(s):  
Glial Cells ◽  
Neurofibromatosis Type 1 ◽  
Neurofibromatosis Type ◽  
Mitogenic Activity

scholarly journals Serum biomarkers for neurofibromatosis type 1 and early detection of malignant peripheral nerve-sheath tumors

BMC Medicine ◽  
2013 ◽  
Vol 11 (1) ◽  
Author(s):  
Su-Jin Park ◽  
Birgit Sawitzki ◽  
Lan Kluwe ◽  
Victor F Mautner ◽  
Nikola Holtkamp ◽  
...  
Keyword(s):  
Early Detection ◽  
Peripheral Nerve ◽  
Neurofibromatosis Type 1 ◽  
Neurofibromatosis Type ◽  
Serum Biomarkers ◽  
Nerve Sheath Tumors ◽  
Peripheral Nerve Sheath Tumors ◽  
Nerve Sheath
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