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PubMed1995

Alternative splicing of the neurofibromatosis 1 gene correlates with growth patterns and neuroendocrine properties of human small-cell lung-carcinoma cells.

Two distinct transcripts, type I and type II, of the neurofibromatosis I (NFI) gene are generated by alternative splicing in the region corresponding to the gene's GTPase-activating protein-related domain (GRD). Relative expression levels of these 2 transcripts were previously correlated to neural differentiation. Since small-cell lung carcinoma (SCLC) often exhibits neuroendocrine properties, we analyzed the type-I to type-II mRNA ratio in 15 SCLC cell lines, using reverse transcriptase and polymerase chain reaction methods. The type-I mRNA was predominant in 10 cell lines; 8 of them grew as floating aggregates in culture and had high L-dopa decarboxylase (DDC) activity. The other 5 lines predominantly expressed type-II mRNA, adhered to the culture substrate, and expressed low or undetectable levels of neural cell-adhesion molecule (NCAM) antigen and DDC activity. N2+, one of the subclones of NCI-N417 cells, exhibited a higher type-I to type-II ratio after the cells had adhered to a laminin-coated plate and had emitted neurite-like processes. These findings provide evidence that alternative splicing patterns of NFI mRNA correlate with the mechanisms that regulate the growth patterns and neuroendocrine properties of SCLC cells in vitro.

Alternative Splicing↗
PubMed1995

Analysis of the GAP-related domain of the neurofibromatosis type 1 (NF1) gene in childhood brain tumors.

The neurofibromatosis type-1 (NF1) gene contains a 360-bp region with significant homology to the catalytic domain of mammalian GTPase-activating protein. This particular GAP-related domain of the NF1 gene (NF1-GRD) stimulates ras GTPase and inactivates ras protein p21ras. Therefore, it has been suggested that the NF1 gene represents another tumor-suppressor gene. In the search for molecular markers of possible diagnostic relevance, childhood brain-tumor specimens of different histologic diagnoses were tested for mutations of the so-called FLR-exon within the NF1-GRD. This part of the NF1-GRD has been shown to be most crucial for the GAP-like function. Using a highly sensitive PCR-SSCP technique, we tested 51 tumor specimens were tested, but found no mutations. We conclude that inactivation of this putative tumor-suppressor gene by mutations does not play a significant role in tumorigenesis of childhood brain tumors. Next, we compared the splice variants of the NF1-GRD in 33 brain tumors and 8 extraneural embryonal tumors. Primitive neuroectodermal tumors (PNET) (n = 10) and one intracranial teratoma were the only tumors that predominantly expressed a splice pattern that can be observed in the immature developing brain. In contrast to other embryonal neuronal tumors, this NF1-GRD splicing pattern could not be modified in a newly established medulloblastoma cell line by retinoic acid treatment. Since this particular splice variant suppresses p21ras more effectively than other NF1-GRD transcripts, its predominant expression may interfere with the physiological signal transduction of p21ras during differentiation of neurons. There may be a neurofibromin-induced and p21ras-mediated differentiation pathway of neuronal stem cells that is blocked in PNET. Such an arrest of a p21ras-dependent differentiation pathway may explain the persistence of primitive pluripotent neuronal cells in PNET.

Alternative Splicing↗
PubMed1991

The GTPase stimulatory activities of the neurofibromatosis type 1 and the yeast IRA2 proteins are inhibited by arachidonic acid.

Three proteins, GTPase activating protein (GAP), neurofibromatosis 1 (NF1) and the yeast inhibitory regulator of the RAS-cAMP pathway (IRA2), have the ability to stimulate the GTPase activity of Ras proteins from higher animals or yeast. Previous studies indicate that certain lipids are able to inhibit this activity associated with the mammalian GAP protein. Inhibition of GAP would be expected to biologically activate Ras protein. In these studies arachidonic acid is shown also to inhibit the activity of the catalytic fragments of the other two proteins, mammalian NF1 and the yeast IRA2 proteins. In addition, phosphatidic acid (containing arachidonic and stearic acid) was inhibitory for the catalytic fragment of NF1 protein, but did not inhibit the catalytic fragments of GAP or IRA2 proteins. These observations emphasize the biochemical similarity of these proteins and provide support for the suggestion that lipids might play an important role in their biological control, and therefore also in the control of Ras activity and cellular proliferation.

Arachidonic Acid↗
PubMed1995

Analysis of cell-mediated mineralization in culture of bone-derived embryonic cells with neurofibromatosis.

von Recklinghausen neurofibromatosis (NF1) is an autosomal dominant genetic disorder associated with congenital pseudoarthrosis and with short stature. To examine whether the NF1 phenotype includes functional osteogenic defects, embryonic bone-derived cells affected with NF1 were tested in culture for specific alkaline phosphatase (ALP) activity and cell-mediated mineralization and compared with other embryonic bone derived cells. NF1 showed a relatively higher specific ALP activity, which has further increased in response to dexamethasone + beta-glycerophosphate (beta GP) (Dex medium) coordinately with a decrease in cell proliferation. In In the control group, two samples showed increased ALP activity, one showed decreased activity and the forth one did not show any change in ALP. NF1 cells were distinguished from other cells regarding day 21 mineralization, they did not mineralize when cultured with ascorbate alone in the absence of Dex medium, whereas control cells did mineralize. Adding beta GP resulted in mineralization by NF1 cells but less than in other cells. In addition, NF1 cells responded to dexamethasone by increasing the beta GP-induced mineralization, as opposed to cells from other embryonic bones, which either did not respond or have even decreased mineralization under dexamethasone. Upon cis-hydroxyproline exposure, Dex medium has also distinguished NF1 cell ALP activity from that of other cell origins. Inhibition of respiratory complex II by malonate showed that most embryonic bone-derived cells of 12 weeks gestation are malonate resistant; thus, malonate selection was ineffective. This is in contrast to rat marrow stromal cells previously shown to undergo mineralizing cell enrichment in response to malonate. Exposure to levamisole, of Dex-treated cells, at days 0-11 has inhibited day 21 mineralization in all tested cultures in spite of the increase in day 11-specific ALP activity. Both malonate and levamisole did not distinguish NF1 cells from the osteogenic phenotype of other cells. Essentially embryonic bone-derived cells from 12 weeks gestation, cultured in the absence of beta GP, retained their mineralization capacity, which does not increase under dexamethasone, as distinguished from NF1 cells which require beta GP for mineralization and positively respond to dexamethasone. Therefore, bone-derived NF1 cells may be useful for studying the regulation of the mineralization process.

Alkaline Phosphatase↗
PubMed1994

Modulation of neurofibromatosis type 1 gene expression during in vitro myoblast differentiation.

Neurofibromin, the protein product of the neurofibromatosis type 1 (NF1) gene, has two alternate isoforms which are generated by alternative splicing of two exons. One of these isoforms containing exon 48a is expressed at highest levels in muscle. Since neurofibromin is a p21-ras regulator and has been recently shown to be modulated during Schwann cell differentiation, we examined the expression of the NF1 gene product during in vitro muscle differentiation. Previous work demonstrated that C2C12 murine myoblast cell differentiation could be blocked by the introduction of an activated p21-ras protein. Using this model system, we demonstrate that differentiating C2C12 cells upregulate the expression of NF1 mRNA by 2 days of serum starvation concomitant with increased expression of nicotinic acetylcholine receptor mRNA. This upregulation of mRNA expression paralleled an increase in neurofibromin and N-ras levels, but no change in the relative abundance of the isoforms containing exon 23a or exon 48a was observed during in vitro myoblast differentiation. The increase in neurofibromin levels paralleled a decrease in the levels of activated p21-ras as assayed by in vivo 32P-orthophosphate incorporation into p21-ras. These results suggest that in vitro C2C12 cell differentiation is associated with a concomitant increase in NF1 gene expression and decrease in the proportion of activated p21-ras.

Animals↗
PubMed1994

Role for the stem cell factor/KIT complex in Schwann cell neoplasia and mast cell proliferation associated with neurofibromatosis.

Schwann cells are the primary cell type in the disfiguring lesions associated with neurofibromatosis type 1 (NF-1). These lesions also contain abnormally high numbers of mast cells, a cell type which develops in response to stem cell factor. We report here that neonatal and adult rat and human Schwann cells, as well as a transfected rat Schwann cell line and a human Schwannoma line derived from an NF-1 patient, all produced stem cell factor mRNA and protein. In coculture experiments, surface expression of stem cell factor by neonatal rat Schwann cells was profoundly downregulated by contact with dorsal root ganglion neurites. The receptor for stem cell factor, KIT, was not expressed in normal Schwann cells but was expressed in the human Schwannoma line, suggesting that aberrant KIT expression may form an autocrine loop in certain Schwann cell neoplasias.

Animals↗
PubMed1992

Alternative splicing of neurofibromatosis type 1 gene transcript in malignant brain tumors: PCR analysis of frozen-section mRNA.

The neurofibromatosis type 1 (NF1) gene encodes a 360-residue region showing significant homology to the catalytic domains of both mammalian GTPase-activating protein (GAP) and yeast IRA protein. The product of the GAP-related domain of the NF1 gene (NF1-GRD) has been shown to stimulate ras GTPase and consequently to inactivate ras protein. We previously reported that the NF1-GRD has two types of transcripts, type I and type II, which are generated by an alternative splicing mechanism, and that the differential splicing of the NF1-GRD may be related to differentiation of neuroectodermal cells. Here we examined the differential expression of type I and type II transcripts of NF1-GRD in clinical samples of supratentorial malignant brain tumors by the RNA-polymerase chain reaction (PCR) method using frozen tissue sections. Our observations revealed that normal cerebrum predominantly expressed the type II NF1-GRD transcript, whereas primitive neuroectodermal tumors predominantly expressed the type I transcript. Additionally, although the type I/type II ratio in astrocytomas varied widely among tissue samples, all glioblastomas showed higher type I/type II ratios than adjacent brain samples. The RNA-PCR analysis using frozen tissue sections is a useful and sensitive method for detecting genetic markers in clinical tissue samples.

Astrocytoma↗
PubMed1993

Carboplatin-induced regression of an optic pathway tumor in a child with neurofibromatosis.

Optic pathway tumors are common in children with neurofibromatosis-1 (NF-1). The optimal management of these tumors is unknown, particularly when the optic chiasm and other brain structures are involved. We report the dramatic response to carboplatin in a 10-year-old girl with NF-1 and a progressive optic pathway tumor. Tumor shrinkage was accompanied by striking improvement in visual fields, return of color discrimination, and marked improvement in visual acuity. No significant toxicity was observed. One year following completion of chemotherapy the glioma remains as small or smaller than it was at the conclusion of therapy, and there has been no deterioration of vision. Carboplatin is a promising agent for the treatment of optic pathway tumors in children with NF-1.

Carboplatin↗
PubMed1994

Neurofibromatosis type I and malignancy: review of 32 pediatric cases treated at a single institution.

Thirty-two cases of neurofibromatosis Type I (NF1) were identified among 6,678 pediatric cancer patients treated at St. Jude Children's Research Hospital over a 29-year period. A total of 35 malignant neoplasms have been diagnosed in these patients. Two of three patients with second malignant neoplasms had colon cancer at the primary or second tumor. Of particular interest are two cases in which both NF1 and malignant peripheral nerve sheath tumors were present in multiple successive generations: a patient with colon cancer and non-Hodgkin lymphoma who has a constitutional abnormality of the p53 gene, and a patient with acute lymphoblastic leukemia with the Philadelphia chromosome and other cytogenetic abnormalities, including the t(8;14). Outcome of patients in the largest subgroup, that of malignant peripheral nerve sheath tumors, was favorable only for those patients having resectable extremity lesions. In contrast, all patients with central nervous system tumors are surviving. These cases reflect the molecular and cytogenetic abnormalities that can be present in NF1 and the variety of tumors that may result in these patients.

Adolescent↗
PubMed1995

Consecutive glioblastoma and B cell non-Hodgkin's lymphoma in a young child with von Recklinghausen's Neurofibromatosis.

A young child with neurofibromatosis type 1 (NF1) is reported who developed two primary malignancies: a glioblastoma, followed 6 months later by an abdominal B cell non-Hodgkin's lymphoma. The child is now 4.5 years off treatment and disease free, but has developed progressive and severe psychomotor retardation as sequelae. The NF1 gene is known to act as a tumor suppressor gene. The possible mechanisms leading to the occurrence of a second primary tumor in this child are discussed.

Abdominal Neoplasms↗
PubMed2006

Brachial plexopathy due to malignant peripheral nerve sheath tumor in neurofibromatosis type 1: case report and subject review.

Neurofibromatosis type 1 (NF1) is a common tumor predisposition syndrome affecting approximately 1 in 4,000 persons. It is an autosomal-dominant disorder with half of the cases resulting from spontaneous mutations. This genetic defect leads to the formation of benign tumors or neurofibromas of the peripheral nervous system. Dermal neurofibromas may cause local discomfort and itching but are rarely associated with neurological deficit and do not undergo malignant change. The more extensive plexiform neurofibromas produce neurological complications in 27%-43% of patients with NF1 and may undergo malignant degeneration in 5% of cases. Patients with NF1 who develop pain or new neurological symptoms should have a rapid and thorough assessment for malignancy. In this report, we illustrate this point by presenting a patient who developed acute shoulder pain and weakness due to malignant degeneration of a plexiform neurofibroma involving the left brachial plexus, and review the literature on this subject.

Brachial Plexus Neuropathies↗
PubMed2006

Primary malignant peripheral nerve sheath tumor of the lung in a young child without neurofibromatosis type 1.

Malignant peripheral nerve sheath tumors (MPNST) are uncommon in children and almost half of the cases occur in patients with neurofibromatosis 1 (NF1). We report a child with a primary MPNST of the lung without NF1. MPNST of the lung has similar clinical and radiologic characteristics as pleuropulmonary blastoma. We suggest to include MPNST of the lung in the differential diagnosis of intrapulmonary masses in children.

Child↗
PubMed2006

Prenatal diagnosis of neurofibromatosis type 1: sonographic and MRI findings.

Prenatal ultrasound and magnetic resonance imaging (MRI) demonstrated a large oropharyngeal tumor, and cardiac and cranial abnormalities consistent with neurofibromatosis type 1 (NF1) in a third-trimester fetus, which were confirmed on postmortem examination. Sonographic features of NF1 are generally nonspecific; MR examination provided significant additional information, facilitating prenatal diagnosis.

Abortion, Induced↗
PubMed1995

Prenatal diagnosis of neurofibromatosis type 1: from flanking RFLPs to intragenic microsatellite markers.

Even though the neurofibromatosis type 1 (NF1) gene was cloned more than 3 years ago, the process of identifying mutations has not been fruitful, and genetic counselling is mainly based on the use of linked markers. Since 1990, we have analysed 130 NF1 families and have performed six prenatal diagnoses. In each case, genetic counselling has relied on linked markers and informativity was achieved in all of them. The use of intragenic microsatellite polymorphisms (IVS27AAAT2.1, IVS27AC28.4, IVS27AC33.1, and IVS38GT53.0) has increased the informativeness in our series of NF1 families to an average of 90 per cent, providing accurate diagnosis and confirmation of the disease status.

Bayes Theorem↗
PubMed1995

Analysis of mutations of neurofibromatosis type 1 gene and N-ras gene in acute myelogenous leukemia.

Neurofibromatosis type 1 (NF1) gene is a tumor suppressor gene, and the NF1 gene product, neurofibromin, can downregulate the N-ras gene. Because the N-ras gene is often mutated in acute myelogenous leukemia (AML), we wondered if the NF1 gene might be mutated in those AML samples not having N-ras mutations. We investigated the mutational status of the N-ras gene and the FLR exon of codons 1371-1423 of the open reading frame of the full-length NF1 cDNA, which has a strong homology with the mammalian ras GTPase-activating protein (GAP), especially for a stretch of three consecutive amino acids (F, L, R), by single-strand conformation polymorphism analysis and direct sequencing in samples from patients with AML. Of 48 AML patients, 10 (21%) had point (missense) mutations of the N-ras gene involving codons 12, 13 and 61. However, mutations in the FLR exon of the NF1 gene were not detected in any of the AML samples. We also examined the difference of clinical response to induction therapy between AML patients with and without N-ras mutation. A significantly lower rate of complete remission was noted in individuals with N-ras gene mutations. These results suggest that mutation of the NF1 gene, at least in the FLR exon, is very rare in AML and the NF1 gene probably is not a functional complement of the N-ras gene mutation. The presence of N-ras gene mutation may be associated with a lower clinical response to antileukemic therapy.

Adult↗
PubMed1994

The growth regulation of neurofibroma cells in neurofibromatosis type-1: increased responses to PDGF-BB and TGF-beta 1.

In neurofibromatosis type-1 (NF-1), abnormal growth regulation may be related to the formation of multiple neurofibromas. We investigated the growth responses of neurofibroma-derived cells (NF cells) and control skin fibroblasts to various growth factors. The responses to platelet-derived growth factor (PDGF-BB) and transforming growth factor-beta 1 (TGF-beta 1) in NF cells were significantly greater than those in control fibroblasts. The increased response to PDGF-BB in NF cells was accompanied by an increased number of PDGF beta receptors, which was demonstrated by both 125I PDGF-BB binding assay and immunoblotting analysis. The increased response to TGF-beta 1 was assumed to be mediated through PDGF-like protein induction; TGF-beta 1-treated NF cells produced greater amounts of 36-kD PDGF-like protein than TGF-beta 1-treated control fibroblasts. These observations suggest that certain growth factors, e.g., PDGF-BB and TGF-beta, may play some role in the development of neurofibromas in NF-1.

Becaplermin↗