Materiały źródłowe

• #1 Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis – UpToDate

  https://www.uptodate.com/contents/neurofibromatosis-type-1-nf1-pathogenesis-clinical-features-and-diagnosis/print

  Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis […] The pathogenesis, clinical features, and diagnosis of NF1 are reviewed here. […] NF1 is an autosomal dominant genetic disorder with an estimated incidence of 1:2600 to 1:3000 individuals. […] The de novo mutations occur primarily in paternally derived chromosomes.

• #2

  https://link.springer.com/article/10.1007/s004390050287

  Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder with a prevalence of around 1 in 3500, affecting all ethnic groups. […] It has been reported that the majority of sporadic mutations in NF1 arise in paternally inherited alleles. […] Our results suggest that in NF1 the majority of deletions occur in oogenesis, while other types of mutations should account for the paternally derived NF1 mutations.

• #3 Neurofibromatosis type 1

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2716546/

  Neurofibromin, the NF1 gene protein product, is a tumor suppressor expressed in many cells, primarily in neurons, glial, Schwann cells and early in melanocyte development. This protein is a regulator of ras guanosine triphosphatase activity (GTPase-activating protein, GAP) and as such serves as a regulator of signals for cell proliferation and differentiation. The loss of function of neurofibromin may therefore remove this regulation, and lead to uncontrolled cell proliferation. Schwann cells in neurofibromas, and melanocytes in caf-au-lait macules have a mutation in both NF1 alleles, including a germline and an acquired somatic mutation and are considered the primary tumor cell in their respective cutaneous manifestation. Based on these findings, it is likely that NF1 functions as a tumor suppressor gene. Both of these cell types are descendants of neural crest. The exact timing of the acquired mutation is unknown but is crucial in the development of the various manifestations; experiments have shown that NF1 gene inactivation at the neural crest stage and mature Schwann cell stage do not lead to tumor formation. However, in a progenitor intermediate step between these two stages, tumor formation occurs with NF1 gene inactivation.

• #4 Neurofibromatosis type 1: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/neurofibromatosis-type-1/

  Neurofibromatosis type 1 is a condition characterized by changes in skin coloring (pigmentation) and the growth of tumors along nerves in the skin, brain, and other parts of the body. […] Mutations in the NF1 gene cause neurofibromatosis type 1. The NF1 gene provides instructions for making a protein called neurofibromin. This protein is produced in many cells, including nerve cells and specialized cells surrounding nerves (oligodendrocytes and Schwann cells). Neurofibromin acts as a tumor suppressor, which means that it keeps cells from growing and dividing too rapidly or in an uncontrolled way. Mutations in the NF1 gene lead to the production of a nonfunctional version of neurofibromin that cannot regulate cell growth and division. As a result, tumors such as neurofibromas can form along nerves throughout the body. […] It is unclear how mutations in the NF1 gene lead to the other features of neurofibromatosis type 1, such as café-au-lait spots and learning disabilities.

• #5 The Pathogenesis of Neurofibromatosis 1 and Neurofibromatosis 2 | Neupsy Key

  https://neupsykey.com/the-pathogenesis-of-neurofibromatosis-1-and-neurofibromatosis-2/

  The two prevailing theories about the pathogenesis of NF1 have something in common: that loss of the genes protein product somehow disrupts the normal sequence of signals responsible for controlling cell division. […] Neurofibromin appears to act as a molecular brake, which is why its loss enables the cell to proliferate out of control. […] The prevailing theory about how neurofibromin functions in the body is that it behaves like a guanosine triphosphatase (GTPase)-activating protein (GAP). Neurofibromin serves to act as a brake on cell proliferation, whereas Ras functions more as a gas pedal. The two are constantly in play to keep cell growth and proliferation balanced and under control. But when the NF1 gene is mutated, there is not enough neurofibromin to counter the actions of Ras. The result is out-of-control cell growth and tumor formation.

• #6 Neurofibromatosis Type 1 and tumorigenesis: molecular mechanisms and therapeutic implications in: Neurosurgical Focus Volume 28 Issue 1 (2010) Journals

  https://thejns.org/focus/view/journals/neurosurg-focus/28/1/article-pE8.xml

  Neurofibromatosis Type 1 (NF1) is a common autosomal dominant disease characterized by complex and multicellular neurofibroma tumors, and less frequently by malignant peripheral nerve sheath tumors (MPNSTs) and optic nerve gliomas. […] Neurofibromatosis Type 1 is caused by germline mutations of the NF1 tumor suppressor gene, which generally result in decreased intracellular neurofibromin protein levels, leading to increased cascade Ras signaling to its downstream effectors. […] Multiple key pathways are involved with the development of tumors in NF1, including Ras/mitogen-activated protein kinase (MAPK) and Akt/mammalian target of rapamycin (mTOR). […] In general, a somatic loss of the second NF1 allele, also referred to as loss of heterozygosity, in the progenitor cell, either the Schwann cell or its precursor, combined with haploinsufficiency in multiple supporting cells is required for tumor formation.

• #7 Neurofibromin – Wikipedia

  https://en.wikipedia.org/wiki/Neurofibromin

  NF1 has one of the highest mutation rates amongst known human genes, however mutation detection is difficult because of its large size, the presence of pseudogenes, and the variety of possible mutations. The NF1 locus has a high incidence of de novo mutations, meaning that the mutations are not inherited maternally or paternally. Although the mutation rate is high, there are no mutation „hot spot” regions. Mutations tend to be distributed within the gene, although exons 3, 5, and 27 are common sites for mutations. […] Through its NF1-GRD domain, neurofibromin increases the rate of GTP hydrolysis of Ras, and acts as a tumor suppressor by reducing Ras activity. When the Ras-Nf1 complex assembles, active Ras binds in a groove that is present in the neurofibromin catalytic domain. This binding occurs through Ras switch regions I and II, and an arginine finger present in neurofibromin. The interaction between Ras and neurofibromin causes GAP-stimulated hydrolysis of GTP to GDP. This process depends on the stabilization of residues in the Ras switch I and switch II regions, which drives Ras into the confirmation required for enzymatic function. This interaction between Ras and neurofibromin also requires the transition state of GDP hydrolysis to be stabilized, which is performed through the insertion of the positively charged arginine finger into the Ras active site. This neutralizes the negative charges that are present on GTP during phosphoryl transfer. By hydrolyzing GTP to GDP, neurofibromin inactivates Ras and therefore negatively regulates the Ras pathway, which controls the expression of genes involved in apoptosis, the cell cycle, cell differentiation or migration.

• #8 Neurofibromin – Wikipedia

  https://en.wikipedia.org/wiki/Neurofibromin

  NF1 has one of the highest mutation rates amongst known human genes, however mutation detection is difficult because of its large size, the presence of pseudogenes, and the variety of possible mutations. The NF1 locus has a high incidence of de novo mutations, meaning that the mutations are not inherited maternally or paternally. Although the mutation rate is high, there are no mutation „hot spot” regions. Mutations tend to be distributed within the gene, although exons 3, 5, and 27 are common sites for mutations. […] Through its NF1-GRD domain, neurofibromin increases the rate of GTP hydrolysis of Ras, and acts as a tumor suppressor by reducing Ras activity. When the Ras-Nf1 complex assembles, active Ras binds in a groove that is present in the neurofibromin catalytic domain. This binding occurs through Ras switch regions I and II, and an arginine finger present in neurofibromin. The interaction between Ras and neurofibromin causes GAP-stimulated hydrolysis of GTP to GDP. This process depends on the stabilization of residues in the Ras switch I and switch II regions, which drives Ras into the confirmation required for enzymatic function. This interaction between Ras and neurofibromin also requires the transition state of GDP hydrolysis to be stabilized, which is performed through the insertion of the positively charged arginine finger into the Ras active site. This neutralizes the negative charges that are present on GTP during phosphoryl transfer. By hydrolyzing GTP to GDP, neurofibromin inactivates Ras and therefore negatively regulates the Ras pathway, which controls the expression of genes involved in apoptosis, the cell cycle, cell differentiation or migration.

• #9 Neurofibromatosis – Wikipedia

  https://en.wikipedia.org/wiki/Neurofibromatosis

  Neurofibromatosis type I is the most common of the three types and is caused by genetic changes in the NF1 gene located on chromosome 17 (17q11.2). This gene encodes a cytoplasmic protein known the neurofibromin, which functions as a tumor suppressor and therefore serves as a signal regulator of cell proliferation and differentiation. A dysfunction or lack of neurofibromin can affect regulation, and cause uncontrolled cell proliferation, leading to the tumors (neurofibromas) that characterize NF1. The neurofibromas caused by NF consist of Schwann cells, fibroblasts, perineuronal cells, mast cells and axons embedded in an extracellular matrix. Another function of neurofibromin is to bind to microtubules that play a role in the release of adenylyl cyclase and its activity. Adenylyl cyclase plays an essential role in cognition. Neurofibromin’s role in the activity of adenylyl cyclase explains why patients with NF experience cognitive impairment.

• #10 Neurofibromatosis type 1 – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/neurofibromatosis-type-1/symptoms-causes/syc-20350490

  Neurofibromatosis type 1 is caused by an altered gene that either is passed down by a parent or occurs at conception. […] The NF1 gene is located on chromosome 17. This gene produces a protein called neurofibromin that helps regulate cell growth. When the gene is altered, it causes a loss of neurofibromin. This allows cells to grow without control.

• #11 Biological pathogenesis, signaling pathways, and therapeutic targets of neurofibromatosis type 1

  https://www.spiedigitallibrary.org/conference-proceedings-of-spie/12924/129240S/Biological-pathogenesis-signaling-pathways-and-therapeutic-targets-of-neurofibromatosis-type/10.1117/12.3013163.full

  The genetic condition neurofibromatosis type 1 (NF-1) shows several different clinical presentations. The cause of the disease is the deletion and mutation of the NF1 tumor suppressor gene, which codes for mutated neurofibromin. The mutation of neurofibromin leads to a decrease in its activity of GAP, thereby promoting the activation of several downstream pathways. The two important downstream pathways of mutant NF1 are RAS/MAPK and Akt/mTOR, which play a critical role in cell growth and survival. The activation of these cellular cascades promotes cell proliferation and migration, further leading to neurofibromatosis type 1. […] Here we focus on the clinical features of neurofibromatosis type 1 and its mechanism of it. Further, we discuss the function and dysfunction of neurofibromin which shows a critical role in the progression of NF-1. Also, we display the downstream pathway of mutant neurofibromin. Importantly, we focus on the clinical application of neurofibromin as the potential therapeutic target of NF-1.

• #12 Neurofibromatosis Type 1 – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK459358/

  Mutations of the NF-1 gene result in a lack of expression of neurofibromin, thereby promoting tumorigenesis. Neurofibromas develop when both NF-1 alleles get mutated. Neurofibromas embody Schwann cells, perineural cells, mast cells, and fibroblasts. […] Neurofibroma originates from the Schwann cell (SC) lineage. […] Neurofibromin normally suppresses guanosine triphosphate (GTP)-bound Kirsten rat sarcoma virus (KRAS). The loss of this function results in the activation of the following: Mitogen-activated protein kinases (MAPKs) and extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2), and Phosphoinositide 3 kinases (PI3K)-mammalian target of rapamycin (mTOR) pathway causing transcription and cellular proliferation. […] Biallelic inactivation of NF1 in SOX10 cells of the SC lineage form neurofibroma. […] The patterns of mutation involved in the pathogenesis include: Frameshift mutations, Nonsense mutations, Missense mutations, Splice-site mutations, and Large deletions. The Syn domain is most commonly affected (80%) in the pathogenesis of NF1.

• #13 Recent advances in Neurofibromatosis type 1 research: Towards tailored therapeutics and treatment strategies

  https://www.e-kjgm.org/journal/view.html?uid=375&&vmd=Full

  Neurofibromatosis type 1 (NF1) is an autosomal dominant multisystem disorder caused by germline mutations in the NF1 gene, classified as a RASopathy. The NF1 gene encodes neurofibromin, a RAS GTPase-activating protein that modulates the Ras-MAPK signaling cascade. […] Loss of NF1 function results in constitutive Ras/Raf/MEK/ERK signaling activation, a primary driver of tumorigenesis in NF1 patients. […] The involvement of the tumor microenvironment (TME) in NF1 pathogenesis is increasingly recognized. Recent advances in single-cell RNA sequencing have delineated the intricate cellular composition and signaling dynamics within mature neurofibromas, elucidating the complexity of the TME. […] Research has demonstrated that schwann cells-immunes (mast cells, T cells) in PNs, microglia and T cells in LGGs, and hematopoietic cells in MPNSTs play a significant role in promoting the development of NF1-associated tumors. […] The distinct functional roles of NF1 isoforms underscore their involvement in various cellular processes and disease mechanisms, making these differences crucial considerations for developing novel therapeutic strategies.

• #14 Neurofibromatosis Type 1 and tumorigenesis: molecular mechanisms and therapeutic implications in: Neurosurgical Focus Volume 28 Issue 1 (2010) Journals

  https://thejns.org/focus/view/journals/neurosurg-focus/28/1/article-pE8.xml

  Neurofibromatosis Type 1 (NF1) is a common autosomal dominant disease characterized by complex and multicellular neurofibroma tumors, and less frequently by malignant peripheral nerve sheath tumors (MPNSTs) and optic nerve gliomas. […] Neurofibromatosis Type 1 is caused by germline mutations of the NF1 tumor suppressor gene, which generally result in decreased intracellular neurofibromin protein levels, leading to increased cascade Ras signaling to its downstream effectors. […] Multiple key pathways are involved with the development of tumors in NF1, including Ras/mitogen-activated protein kinase (MAPK) and Akt/mammalian target of rapamycin (mTOR). […] In general, a somatic loss of the second NF1 allele, also referred to as loss of heterozygosity, in the progenitor cell, either the Schwann cell or its precursor, combined with haploinsufficiency in multiple supporting cells is required for tumor formation.

• #15 Translating current basic research into future therapies for neurofibromatosis type 1 | British Journal of Cancer

  https://www.nature.com/articles/s41416-020-0903-x

  Neurofibromatosis type 1 (NF1) is a hereditary tumour syndrome that predisposes to benign and malignant tumours originating from neural crest cells. […] Biallelic inactivation of the tumour-suppressor gene NF1 in glial cells in the skin, along a nerve plexus or in the brain results in the development of benign tumours: cutaneous neurofibroma, plexiform neurofibroma and glioma, respectively. […] Despite more than 40 years of research, only one medication was recently approved for treatment of plexiform neurofibroma and no drugs have been specifically approved for the management of other tumours. […] Work carried out over the past several years indicates that inhibiting different cellular signalling pathways (such as Hippo, Janus kinase/signal transducer and activator of transcription, mitogen-activated protein kinase and those mediated by sex hormones) in tumour cells or targeting cells in the microenvironment (nerve cells, macrophages, mast cells and T cells) might benefit NF1 patients.

• #16 Translating current basic research into future therapies for neurofibromatosis type 1 | British Journal of Cancer

  https://www.nature.com/articles/s41416-020-0903-x

  Neurofibromatosis type 1 (NF1) is a hereditary tumour syndrome that predisposes to benign and malignant tumours originating from neural crest cells. […] Biallelic inactivation of the tumour-suppressor gene NF1 in glial cells in the skin, along a nerve plexus or in the brain results in the development of benign tumours: cutaneous neurofibroma, plexiform neurofibroma and glioma, respectively. […] Despite more than 40 years of research, only one medication was recently approved for treatment of plexiform neurofibroma and no drugs have been specifically approved for the management of other tumours. […] Work carried out over the past several years indicates that inhibiting different cellular signalling pathways (such as Hippo, Janus kinase/signal transducer and activator of transcription, mitogen-activated protein kinase and those mediated by sex hormones) in tumour cells or targeting cells in the microenvironment (nerve cells, macrophages, mast cells and T cells) might benefit NF1 patients.

• #17 Translating current basic research into future therapies for neurofibromatosis type 1 | British Journal of Cancer

  https://www.nature.com/articles/s41416-020-0903-x

  Recent advances in our understanding of tumour molecular and cellular pathogenesis will provide opportunities to develop effective treatments in the future for NF1-associated neoplasms. […] The Hippo pathway acts as a modifier and a driver, respectively, suggesting that selectively dampening the Hippo pathway using inhibitors could be an attractive therapeutic approach. […] Signalling through the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is known to contribute to tumorigenesis in numerous ways. […] In brief, interfering with the STAT3 pathway delayed neurofibroma initiation as well as progression to MPNST, but had far less impact on tumour maintenance. […] The existence of mouse models in the NF1 arena has provided unprecedented opportunities to derive important insights into the biology of the disease as well as preclinical models that guide the development of effective therapies for NF1.

• #18

  https://journals.lww.com/ijpm/fulltext/2020/63010/first_case_report_of_tongue_squamous_cell.26.aspx

  Neurofibromin downregulates RAS by conversion of guanosine triphosphate to guanosine diphosphate. […] When there is a lack of expression of neurofibromin protein due to mutated NF1 gene, the inhibitory signal over the RAS/MAPK pathway is lost resulting in uninterrupted transmission of mitogenic signals to the nucleus, thereby resulting in uncontrolled proliferation. […] WNT signaling pathway activation has also been investigated in the context of carcinogenesis in NF1. […] The study also showed that there was increased expression of active beta-catenin protein when NF1 was silenced. […] So, they concluded and tried to establish that NF1 alters WNT pathway and favors tumorigenesis. […] Another protein, heat shock factor 1 (HSF1), is overexpressed in NF1, which helps in combating the intrinsic stresses produced within the tumor cells, there by favoring their survival.

• #19 Neurofibromatosis Type 1 | Concise Medical Knowledge

  https://www.lecturio.com/concepts/neurofibromatosis-type-1/

  Mutations in the NF1 gene located on chromosome 17. […] NF1 encodes neurofibromin, a cytoplasmic protein. […] Multidomain molecule regulating several important intracellular processes: RAS-cyclic AMP pathway, Extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) cascade, Adenylyl cyclase, Cytoskeletal assembly. […] Also functions as a tumor suppressor. […] Involvement of neurofibromin in various pathways explains the wide range of clinical manifestations.

• #20 Neurofibromatosis type 1-associated tumours: Their somatic mutational spectrum and pathogenesis | Human Genomics | Full Text

  https://humgenomics.biomedcentral.com/articles/10.1186/1479-7364-5-6-623

  The NF1 gene encodes neurofibromin, a negative regulator of the Ras/mitogen-activated protein kinase (MAPK) pathway. NF1 is a TSG and, consistent with Knudson’s two-hit hypothesis, most patients carry (in all their cells) both a normal and a dysfunctional NF1 gene copy — the latter harbouring the inherited (germline) mutation. It may be inferred that any tumours that arise will have acquired a second, somatic 'hit’ that inactivates the normal NF1 allele, resulting in a complete loss of functional neurofibromin; a double hit (NF1-/-) is critical for NF1 tumorigenesis to occur. […] The question as to why only a few of these benign tumours eventually go on to become malignant, however, is still puzzling. […] An appreciation of the spectrum of somatic mutations in NF1-associated tumours is therefore essential if we are to understand the molecular pathways involved — itself a prerequisite for improvements in clinical treatment and the development of new therapeutics.

• #21 Neurofibromatosis: Types 1 and 2 | American Journal of Neuroradiology

  https://www.ajnr.org/content/34/12/2250

  Neurofibromatosis type 1 is seen in 1 of 3000-5000 people across the world. This disease was first described in 1882 by von Recklinghausen, leading to the initial name of the condition, von Recklinghausen disease. The condition is manifested by a constellation of neurocutaneous tumors and vasculitis. […] NF1 is thought to cause disease by following characteristics of the two-hit hypothesis, first described by Alfred Knudson in 1971. All patients with NF1 are heterozygous for the NF1 mutation, and it is thought that somatic mutations lead to the development of tumors by causing a loss of heterozygosity. The mutation most often results in truncation of neurofibromin, though 500 types of mutations have been described. While the precise mechanisms are still being discovered, current hypotheses support the notion that a somatic mutation results in a second hit, leading to a loss in regulation of the cell cycle and resultant tumors.

• #22 Neurofibromatosis type 1-associated tumours: Their somatic mutational spectrum and pathogenesis | Human Genomics | Full Text

  https://humgenomics.biomedcentral.com/articles/10.1186/1479-7364-5-6-623

  The molecular mechanisms underlying both PNF and cutaneous neurofibroma formation are becoming clearer, although the major details are still lacking. It would appear that the key to understanding neurofibroma formation lies in the elucidation of the precise molecular interactions of the haploinsufficient tumour microenvironment within the initial cell type harbouring the biallelically inactivated NF1 gene. […] Although it is clear that biallelic NF1 gene inactivation is required for transformation to occur, mutations at the NF1 locus are insufficient to explain the process of tumorigenesis, as most benign neurofibromas also exhibit such biallelic NF1 inactivation. […] The best evidence for the involvement of other loci relates to the tumour protein 53 gene (TP53), for which several different mutations have been found in MPNSTs that have not been reported in benign neurofibromas.

• #23 Neurofibromatosis type 1-associated tumours: Their somatic mutational spectrum and pathogenesis | Human Genomics | Full Text

  https://humgenomics.biomedcentral.com/articles/10.1186/1479-7364-5-6-623

  The homozygous loss of the cyclin-dependent kinase inhibitor 2A gene (CDKN2A), which encodes p16INK4A and p14ARF, has also been associated with NF1 malignancy. […] The aberrant molecular pathways that underlie this malignant transformation are still largely unknown, and considerable effort is being directed towards elucidating the molecular defects involved. […] This review demonstrates that NF1-associated tumour types display a considerable degree of variation in terms of the level of LOH detected, with cutaneous neurofibromas, PNFs and MPNSTs. MPNSTs manifest increased levels of deletion-based LOH, whereas cutaneous neurofibromas appear to be associated with a localised deletion of the NF1 gene through mitotic recombination (the situation in PNFs being somewhat intermediate). In MPNSTs, additional mutations at different gene loci are almost certainly involved in the progression of the tumour.

• #24 Neurofibromatosis type 1-associated tumours: Their somatic mutational spectrum and pathogenesis | Human Genomics | Full Text

  https://humgenomics.biomedcentral.com/articles/10.1186/1479-7364-5-6-623

  The homozygous loss of the cyclin-dependent kinase inhibitor 2A gene (CDKN2A), which encodes p16INK4A and p14ARF, has also been associated with NF1 malignancy. […] The aberrant molecular pathways that underlie this malignant transformation are still largely unknown, and considerable effort is being directed towards elucidating the molecular defects involved. […] This review demonstrates that NF1-associated tumour types display a considerable degree of variation in terms of the level of LOH detected, with cutaneous neurofibromas, PNFs and MPNSTs. MPNSTs manifest increased levels of deletion-based LOH, whereas cutaneous neurofibromas appear to be associated with a localised deletion of the NF1 gene through mitotic recombination (the situation in PNFs being somewhat intermediate). In MPNSTs, additional mutations at different gene loci are almost certainly involved in the progression of the tumour.

• #25 Neurofibromatosis type 1-associated tumours: Their somatic mutational spectrum and pathogenesis | Human Genomics | Full Text

  https://humgenomics.biomedcentral.com/articles/10.1186/1479-7364-5-6-623

  The homozygous loss of the cyclin-dependent kinase inhibitor 2A gene (CDKN2A), which encodes p16INK4A and p14ARF, has also been associated with NF1 malignancy. […] The aberrant molecular pathways that underlie this malignant transformation are still largely unknown, and considerable effort is being directed towards elucidating the molecular defects involved. […] This review demonstrates that NF1-associated tumour types display a considerable degree of variation in terms of the level of LOH detected, with cutaneous neurofibromas, PNFs and MPNSTs. MPNSTs manifest increased levels of deletion-based LOH, whereas cutaneous neurofibromas appear to be associated with a localised deletion of the NF1 gene through mitotic recombination (the situation in PNFs being somewhat intermediate). In MPNSTs, additional mutations at different gene loci are almost certainly involved in the progression of the tumour.

• #26 Neurofibromatosis type 1

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2716546/

  Neurofibromin, the NF1 gene protein product, is a tumor suppressor expressed in many cells, primarily in neurons, glial, Schwann cells and early in melanocyte development. This protein is a regulator of ras guanosine triphosphatase activity (GTPase-activating protein, GAP) and as such serves as a regulator of signals for cell proliferation and differentiation. The loss of function of neurofibromin may therefore remove this regulation, and lead to uncontrolled cell proliferation. Schwann cells in neurofibromas, and melanocytes in caf-au-lait macules have a mutation in both NF1 alleles, including a germline and an acquired somatic mutation and are considered the primary tumor cell in their respective cutaneous manifestation. Based on these findings, it is likely that NF1 functions as a tumor suppressor gene. Both of these cell types are descendants of neural crest. The exact timing of the acquired mutation is unknown but is crucial in the development of the various manifestations; experiments have shown that NF1 gene inactivation at the neural crest stage and mature Schwann cell stage do not lead to tumor formation. However, in a progenitor intermediate step between these two stages, tumor formation occurs with NF1 gene inactivation.

• #27 Neurofibroma Development in Neurofibromatosis Type 1: Insights from Cellular Origin and Schwann Cell Lineage Development

  https://www.mdpi.com/2072-6694/14/18/4513

  Neurofibromas have been thought to originate from cells within the Schwann cell lineage, while no consensus has been reached so far about the specific time of initiation and the exact cellular origin. […] Neurofibromatosis type 1 (NF1), a genetic tumor predisposition syndrome that affects about 1 in 3000 newborns, is caused by mutations in the NF1 gene and subsequent inactivation of its encoded neurofibromin. Neurofibromin is a tumor suppressor protein involved in the downregulation of Ras signaling. […] The distinct spatiotemporal characteristics of plexiform and cutaneous neurofibromas have prompted hypotheses about the origin and developmental features of these tumors, involving various cellular transition processes. […] We highlighted the Schwann cell (SC) lineage shift to better present the evolution of its corresponding cellular origin hypothesis and its important effects on the progression and malignant transformation of neurofibromas.

• #28 Neurofibromatosis type 1

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2716546/

  Neurofibromin, the NF1 gene protein product, is a tumor suppressor expressed in many cells, primarily in neurons, glial, Schwann cells and early in melanocyte development. This protein is a regulator of ras guanosine triphosphatase activity (GTPase-activating protein, GAP) and as such serves as a regulator of signals for cell proliferation and differentiation. The loss of function of neurofibromin may therefore remove this regulation, and lead to uncontrolled cell proliferation. Schwann cells in neurofibromas, and melanocytes in caf-au-lait macules have a mutation in both NF1 alleles, including a germline and an acquired somatic mutation and are considered the primary tumor cell in their respective cutaneous manifestation. Based on these findings, it is likely that NF1 functions as a tumor suppressor gene. Both of these cell types are descendants of neural crest. The exact timing of the acquired mutation is unknown but is crucial in the development of the various manifestations; experiments have shown that NF1 gene inactivation at the neural crest stage and mature Schwann cell stage do not lead to tumor formation. However, in a progenitor intermediate step between these two stages, tumor formation occurs with NF1 gene inactivation.

• #29 Neurofibromatosis type 1

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2716546/

  Neurofibromin, the NF1 gene protein product, is a tumor suppressor expressed in many cells, primarily in neurons, glial, Schwann cells and early in melanocyte development. This protein is a regulator of ras guanosine triphosphatase activity (GTPase-activating protein, GAP) and as such serves as a regulator of signals for cell proliferation and differentiation. The loss of function of neurofibromin may therefore remove this regulation, and lead to uncontrolled cell proliferation. Schwann cells in neurofibromas, and melanocytes in caf-au-lait macules have a mutation in both NF1 alleles, including a germline and an acquired somatic mutation and are considered the primary tumor cell in their respective cutaneous manifestation. Based on these findings, it is likely that NF1 functions as a tumor suppressor gene. Both of these cell types are descendants of neural crest. The exact timing of the acquired mutation is unknown but is crucial in the development of the various manifestations; experiments have shown that NF1 gene inactivation at the neural crest stage and mature Schwann cell stage do not lead to tumor formation. However, in a progenitor intermediate step between these two stages, tumor formation occurs with NF1 gene inactivation.

• #30 Neurofibroma Development in Neurofibromatosis Type 1: Insights from Cellular Origin and Schwann Cell Lineage Development

  https://www.mdpi.com/2072-6694/14/18/4513

  The specific subpopulation acting as the cellular origin of cNF remained unknown. […] The activation of the N-Ras signaling pathway expressed in neural crest-derived cells caused cNF formation. […] The loss of Nf1 in SCs at E12.5 was sufficient to give rise to both pNF and cNF in a wild-type microenvironment. […] The previous concept of distinctive initiation stages was transformed to that of a shared initiation stage. […] The explanation for the difference in the timing and location of occurrence was the spatiotemporal difference in NF1 loss at subsequent developmental stages. […] The underlying mechanism involves Ras-dependent downregulation of an SC surface protein, semaphorin 4F (Sema4F), together with elevated inflammatory signals, especially upon injury. […] The proliferative state of neoplastic cells and supportive tumor microenvironment combined to promote neurofibroma progression.

• #31 Neurofibroma Development in Neurofibromatosis Type 1: Insights from Cellular Origin and Schwann Cell Lineage Development

  https://www.mdpi.com/2072-6694/14/18/4513

  The specific subpopulation acting as the cellular origin of cNF remained unknown. […] The activation of the N-Ras signaling pathway expressed in neural crest-derived cells caused cNF formation. […] The loss of Nf1 in SCs at E12.5 was sufficient to give rise to both pNF and cNF in a wild-type microenvironment. […] The previous concept of distinctive initiation stages was transformed to that of a shared initiation stage. […] The explanation for the difference in the timing and location of occurrence was the spatiotemporal difference in NF1 loss at subsequent developmental stages. […] The underlying mechanism involves Ras-dependent downregulation of an SC surface protein, semaphorin 4F (Sema4F), together with elevated inflammatory signals, especially upon injury. […] The proliferative state of neoplastic cells and supportive tumor microenvironment combined to promote neurofibroma progression.

• #32 NF1 gene: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/gene/nf1/

  The NF1 gene provides instructions for making a protein called neurofibromin. This protein is produced in many types of cells, including nerve cells and specialized cells called oligodendrocytes and Schwann cells that surround nerves. […] Neurofibromin acts as a tumor suppressor protein. Tumor suppressors normally prevent cells from growing and dividing too rapidly or in an uncontrolled way. This protein appears to prevent cell overgrowth by turning off another protein (called ras) that stimulates cell growth and division. […] More than 1,000 NF1 mutations that cause neurofibromatosis type 1 have been identified. Most of these mutations are unique to a particular family. Many NF1 mutations result in the production of an extremely short version of neurofibromin. This shortened protein cannot perform its normal job of inhibiting cell division. When mutations occur in both copies of the NF1 gene in Schwann cells, the resulting loss of neurofibromin allows noncancerous tumors called neurofibromas to form. Research indicates that the formation of neurofibromas requires the interaction of Schwann cells with other cells, including mast cells. […] In rare cases, inactivation of one copy of the NF1 gene in each cell increases the risk of developing juvenile myelomonocytic leukemia (JMML).

• #33 Translating current basic research into future therapies for neurofibromatosis type 1 | British Journal of Cancer

  https://www.nature.com/articles/s41416-020-0903-x

  Neurofibromatosis type 1 (NF1) is a hereditary tumour syndrome that predisposes to benign and malignant tumours originating from neural crest cells. […] Biallelic inactivation of the tumour-suppressor gene NF1 in glial cells in the skin, along a nerve plexus or in the brain results in the development of benign tumours: cutaneous neurofibroma, plexiform neurofibroma and glioma, respectively. […] Despite more than 40 years of research, only one medication was recently approved for treatment of plexiform neurofibroma and no drugs have been specifically approved for the management of other tumours. […] Work carried out over the past several years indicates that inhibiting different cellular signalling pathways (such as Hippo, Janus kinase/signal transducer and activator of transcription, mitogen-activated protein kinase and those mediated by sex hormones) in tumour cells or targeting cells in the microenvironment (nerve cells, macrophages, mast cells and T cells) might benefit NF1 patients.

• #34 Immune system changes in the pathogenesis of neurofibromatosis type 1

  https://ouci.dntb.gov.ua/en/works/7pbq8PBl/

  Neurofibromatosis type 1 (NF1) is caused by germline heterozygous mutations in the NF1 gene, which encodes the oncosuppressor neurofibromin. […] The deficiency of neurofibromin impairs the differentiation and correct functioning of immune system cells. […] The development of neurofibromas is associated with the fact that NF1–/– Schwann cells stimulate the migration of mast cells into the tumor microenvironment, which actively degranulate. […] Therefore, in the treatment of NF1, the use of ketotifen and a kit/fms kinase inhibitor is recommended. […] Macrophages and T-lymphocytes in neurofibromas do not provide an antitumor response, but promote inflammation and tumor growth. […] Therefore, a promising direction is NF1 therapy with STAT3 inhibitors and immune checkpoint inhibitors that block programmed cell death ligand 1 (PD-L1).

• #35 Immune system changes in the pathogenesis of neurofibromatosis type 1

  https://ouci.dntb.gov.ua/en/works/7pbq8PBl/

  Neurofibromatosis type 1 (NF1) is caused by germline heterozygous mutations in the NF1 gene, which encodes the oncosuppressor neurofibromin. […] The deficiency of neurofibromin impairs the differentiation and correct functioning of immune system cells. […] The development of neurofibromas is associated with the fact that NF1–/– Schwann cells stimulate the migration of mast cells into the tumor microenvironment, which actively degranulate. […] Therefore, in the treatment of NF1, the use of ketotifen and a kit/fms kinase inhibitor is recommended. […] Macrophages and T-lymphocytes in neurofibromas do not provide an antitumor response, but promote inflammation and tumor growth. […] Therefore, a promising direction is NF1 therapy with STAT3 inhibitors and immune checkpoint inhibitors that block programmed cell death ligand 1 (PD-L1).

• #36

  https://www.nfnetwork.org/pages-news/investigating-the-role-of-fibroblasts-in-the-pathogenesis-in-neurofibromas/?lang=en

  Dr. Le and his team demonstrated that an Nf1+/- microenvironment accelerates benign tumor formation, but impairs further progression to malignancy in two independent mouse models representing NF1- and non-NF1-associated tumors. […] Dr. Le was also awarded an FY16 Investigator-Initiated Research Award through the NFRP to define molecular and developmental pathogenesis of Schwann cell tumors and elucidate the mechanisms by which specific cancer pathways may affect tumor formation. […] The most recent publication by Dr. Le and his group describes the role of HOXB7 as a lineage marker in mapping the origin of neoplastic cells within cutaneous neurofibroma (cNF), the most common tumor in NF1 patients. […] Furthermore, this work demonstrated that neurofibroma tumorigenesis is susceptible to modification through modulation of the Hippo pathway, a signaling pathway that controls cell growth and has been implicated in numerous cancer types.

• #37 Recent advances in Neurofibromatosis type 1 research: Towards tailored therapeutics and treatment strategies

  https://www.e-kjgm.org/journal/view.html?uid=375&&vmd=Full

  Neurofibromatosis type 1 (NF1) is an autosomal dominant multisystem disorder caused by germline mutations in the NF1 gene, classified as a RASopathy. The NF1 gene encodes neurofibromin, a RAS GTPase-activating protein that modulates the Ras-MAPK signaling cascade. […] Loss of NF1 function results in constitutive Ras/Raf/MEK/ERK signaling activation, a primary driver of tumorigenesis in NF1 patients. […] The involvement of the tumor microenvironment (TME) in NF1 pathogenesis is increasingly recognized. Recent advances in single-cell RNA sequencing have delineated the intricate cellular composition and signaling dynamics within mature neurofibromas, elucidating the complexity of the TME. […] Research has demonstrated that schwann cells-immunes (mast cells, T cells) in PNs, microglia and T cells in LGGs, and hematopoietic cells in MPNSTs play a significant role in promoting the development of NF1-associated tumors. […] The distinct functional roles of NF1 isoforms underscore their involvement in various cellular processes and disease mechanisms, making these differences crucial considerations for developing novel therapeutic strategies.

• #38

  https://www.nfnetwork.org/pages-news/investigating-the-role-of-fibroblasts-in-the-pathogenesis-in-neurofibromas/?lang=en

  Dr. Le and his team demonstrated that an Nf1+/- microenvironment accelerates benign tumor formation, but impairs further progression to malignancy in two independent mouse models representing NF1- and non-NF1-associated tumors. […] Dr. Le was also awarded an FY16 Investigator-Initiated Research Award through the NFRP to define molecular and developmental pathogenesis of Schwann cell tumors and elucidate the mechanisms by which specific cancer pathways may affect tumor formation. […] The most recent publication by Dr. Le and his group describes the role of HOXB7 as a lineage marker in mapping the origin of neoplastic cells within cutaneous neurofibroma (cNF), the most common tumor in NF1 patients. […] Furthermore, this work demonstrated that neurofibroma tumorigenesis is susceptible to modification through modulation of the Hippo pathway, a signaling pathway that controls cell growth and has been implicated in numerous cancer types.

• #39 Rationale for haploinsufficiency correction therapy in neurofibromatosis type 1

  https://www.oaepublish.com/articles/jtgg.2022.14

  Neurofibromatosis type 1 (NF1) is a genetic disorder with a wide range of manifestations and severity. Currently, the few available NF1 treatments target specific manifestations, with no available therapies targeted to correct the underlying driver of all NF1 manifestations. Evidence supports that haploinsufficiency in NF1 caused by a decreased amount of wild-type (WT) neurofibromin in all NF1+/- cells directly causes or facilitates a range of NF1 manifestations. Consequently, NF1 haploinsufficiency correction therapy (NF1-HCT) represents a potentially effective approach to treat some NF1 manifestations. NF1-HCT would normalize the level of WT neurofibromin in all NF1-haploinsufficient cells, including those integral to the NF1 phenotype such as Schwann cells (SCs), melanocytes, neurons, bone cells, and cells of the tumor microenvironment. This would correct altered cellular signaling pathways and, in turn, restore normal function to cells with a retained WT allele. NF1-HCT will not restore WT neurofibromin in NF1-/- cells; however, by restoring function in the surrounding NF1+/- microenvironment cells, NF1-HCT is predicted to have a beneficial effect on NF1-/- cells. NF1-HCT is expected to have a clinical effect in some NF1 manifestations, as follows: (i) prevention, or delay of onset, of potential manifestations; and (ii) reversal, or halting/slowing progression, of established manifestations.

• #40 Neurofibromatosis type I – wikidoc

  https://www.wikidoc.org/index.php/Neurofibromatosis_type_I

  Neurofibromatosis type 1 is an autosomal syndrome, although, roughly 50% of gene mutations arise from de novo events. […] The large size of the NF1 gene (350 kb with 60 exons) predisposes to a high mutation rate, with approximately one mutation occurring per 10,000 gametes. […] NF1 mutations lead to protein truncation (loss of neurofibromin expression), which in turn produces increased cell growth and survival through expression of RAS to ultimately increase chances for malignant transformation. […] More than 3,000 NF1 gene mutations have been recognised. […] Loss of neurofibromin leads to formation of skin lesions, tumours and skeletal abnormalities. […] Patients with neurofibromatosis type 1 syndrome have a higher incidence of GI, liver, lung, bone, thyroid, breast and ovarian cancers.

• #41 Neurofibromatosis type 1-associated tumours: Their somatic mutational spectrum and pathogenesis | Human Genomics | Full Text

  https://humgenomics.biomedcentral.com/articles/10.1186/1479-7364-5-6-623

  The molecular mechanisms underlying both PNF and cutaneous neurofibroma formation are becoming clearer, although the major details are still lacking. It would appear that the key to understanding neurofibroma formation lies in the elucidation of the precise molecular interactions of the haploinsufficient tumour microenvironment within the initial cell type harbouring the biallelically inactivated NF1 gene. […] Although it is clear that biallelic NF1 gene inactivation is required for transformation to occur, mutations at the NF1 locus are insufficient to explain the process of tumorigenesis, as most benign neurofibromas also exhibit such biallelic NF1 inactivation. […] The best evidence for the involvement of other loci relates to the tumour protein 53 gene (TP53), for which several different mutations have been found in MPNSTs that have not been reported in benign neurofibromas.

• #42 Neurofibromatosis type 1-associated tumours: Their somatic mutational spectrum and pathogenesis | Human Genomics | Full Text

  https://humgenomics.biomedcentral.com/articles/10.1186/1479-7364-5-6-623

  The molecular mechanisms underlying both PNF and cutaneous neurofibroma formation are becoming clearer, although the major details are still lacking. It would appear that the key to understanding neurofibroma formation lies in the elucidation of the precise molecular interactions of the haploinsufficient tumour microenvironment within the initial cell type harbouring the biallelically inactivated NF1 gene. […] Although it is clear that biallelic NF1 gene inactivation is required for transformation to occur, mutations at the NF1 locus are insufficient to explain the process of tumorigenesis, as most benign neurofibromas also exhibit such biallelic NF1 inactivation. […] The best evidence for the involvement of other loci relates to the tumour protein 53 gene (TP53), for which several different mutations have been found in MPNSTs that have not been reported in benign neurofibromas.

• #43 Neurofibromatosis type 1-associated tumours: Their somatic mutational spectrum and pathogenesis | Human Genomics | Full Text

  https://humgenomics.biomedcentral.com/articles/10.1186/1479-7364-5-6-623

  The homozygous loss of the cyclin-dependent kinase inhibitor 2A gene (CDKN2A), which encodes p16INK4A and p14ARF, has also been associated with NF1 malignancy. […] The aberrant molecular pathways that underlie this malignant transformation are still largely unknown, and considerable effort is being directed towards elucidating the molecular defects involved. […] This review demonstrates that NF1-associated tumour types display a considerable degree of variation in terms of the level of LOH detected, with cutaneous neurofibromas, PNFs and MPNSTs. MPNSTs manifest increased levels of deletion-based LOH, whereas cutaneous neurofibromas appear to be associated with a localised deletion of the NF1 gene through mitotic recombination (the situation in PNFs being somewhat intermediate). In MPNSTs, additional mutations at different gene loci are almost certainly involved in the progression of the tumour.

• #44

  https://scite.ai/reports/10.1097/pap.0000000000000197

  In addition, whereas pNF occasionally transform into malignant peripheral nerve sheath tumors, cNF have little, if any, malignant potential. Finally, whereas pNF clearly originate within nerves and plexuses, the origin of cNF remains uncertain particularly in relation to cutaneous innervation. […] A number of mutations that drive MPNST pathogenesis have been identified, with a surprising degree of overlap in NF1-associated and sporadic forms. These include molecular variants of the NF1 tumor suppressor gene that are present in all NF1 patients, and in a majority of sporadic and radiation-induced MPNSTs. Other ancillary, yet essential, cancer-driving genetic aberrations include loss of the genes CDKN2A, TP53, RB, or PTEN, or the genes encoding the PRC2 components SUZ12 or EED, and amplification of PDGFRA, EGFR, or MET.

• #45

  https://scite.ai/reports/10.1097/pap.0000000000000197

  In addition, whereas pNF occasionally transform into malignant peripheral nerve sheath tumors, cNF have little, if any, malignant potential. Finally, whereas pNF clearly originate within nerves and plexuses, the origin of cNF remains uncertain particularly in relation to cutaneous innervation. […] A number of mutations that drive MPNST pathogenesis have been identified, with a surprising degree of overlap in NF1-associated and sporadic forms. These include molecular variants of the NF1 tumor suppressor gene that are present in all NF1 patients, and in a majority of sporadic and radiation-induced MPNSTs. Other ancillary, yet essential, cancer-driving genetic aberrations include loss of the genes CDKN2A, TP53, RB, or PTEN, or the genes encoding the PRC2 components SUZ12 or EED, and amplification of PDGFRA, EGFR, or MET.

• #46 Translating current basic research into future therapies for neurofibromatosis type 1 | British Journal of Cancer

  https://www.nature.com/articles/s41416-020-0903-x

  However, a pNF can progress into an atypical neurofibromatous neoplasm of uncertain biological potential (ANNUBP) typically as a result of a subsequent genetic mutation in CDKN2A and, upon further genetic insult to additional tumour-suppressor genes, such as TP53, PTEN or members of the PRC2 chromatin-remodelling complex, an ANNUBP or a pNF can transform into a MPNST. […] The lifetime risk of developing MPNSTs is 8-13% in all patients with NF1, although this risk is higher in patients with pNFs. […] NF1 patients can also develop OPGs. […] The microenvironment of OPGs is very heterogeneous and plays an essential role in tumorigenesis as in neurofibromas. […] Several studies have demonstrated that OPG tumour cell proliferation is largely dependent on the microglia, which secrete chemokine ligands to recruit more microglia and to induce the proliferation of astroglial tumour cells.

• #47 Neurofibroma Development in Neurofibromatosis Type 1: Insights from Cellular Origin and Schwann Cell Lineage Development

  https://www.mdpi.com/2072-6694/14/18/4513

  The specific time of initiation and exact cellular origin of pNFs and cNFs remain controversial, despite intensive studies. […] Recent studies using genetically engineered mouse (GEM) models have shed light on the development of SC lineages. […] The significant differences between these two subtypes of neurofibromas and the phenomenon that mouse models develop pNF but fail to develop cNF at 100% frequency jointly indicate that the cellular origins of these lesions may differ. […] The study progress of the cellular origin of both pNF and cNF is summarized in Table 1. […] The cutaneous form of NF occurs in almost all NF1 patients, with tumors typically emerging around puberty and potentially increasing in number over the lifespan of the patients. […] The capability of SKPs to express Dhh and generate both pNF and cNF was identified.

• #48

  https://scite.ai/reports/10.1097/pap.0000000000000197

  Multiple cutaneous neurofibromas (cNF) are characteristic of neurofibromatosis type 1 (NF1) patients who have an autosomal dominant loss-of-function mutation of an NF1 allele. cNF are visibly protruding masses in the skin composed of a complex mixture of hyperproliferating Schwann cells (SC), particularly nonmyelinating SC (nSC), intermingled with fibroblasts, vasculature, macrophages, mast cells and other cellular components. This composition is similar to another hallmark of NF1, which are the expansive growths within large nerves and plexuses referred to as plexiform neurofibromas (pNF). […] Although their histologic and genomic abnormalities are similar, the natural history of cNF and pNF is quite distinct. While pNF often present as congenital lesions, cNF are typically not present at birth. Instead, cNF usually begin to appear at puberty, accumulating thereafter to a variable degree over the remainder of the patients life.

• #49

  https://scite.ai/reports/10.1097/pap.0000000000000197

  Multiple cutaneous neurofibromas (cNF) are characteristic of neurofibromatosis type 1 (NF1) patients who have an autosomal dominant loss-of-function mutation of an NF1 allele. cNF are visibly protruding masses in the skin composed of a complex mixture of hyperproliferating Schwann cells (SC), particularly nonmyelinating SC (nSC), intermingled with fibroblasts, vasculature, macrophages, mast cells and other cellular components. This composition is similar to another hallmark of NF1, which are the expansive growths within large nerves and plexuses referred to as plexiform neurofibromas (pNF). […] Although their histologic and genomic abnormalities are similar, the natural history of cNF and pNF is quite distinct. While pNF often present as congenital lesions, cNF are typically not present at birth. Instead, cNF usually begin to appear at puberty, accumulating thereafter to a variable degree over the remainder of the patients life.

• #50

  https://scite.ai/reports/10.1097/pap.0000000000000197

  Multiple cutaneous neurofibromas (cNF) are characteristic of neurofibromatosis type 1 (NF1) patients who have an autosomal dominant loss-of-function mutation of an NF1 allele. cNF are visibly protruding masses in the skin composed of a complex mixture of hyperproliferating Schwann cells (SC), particularly nonmyelinating SC (nSC), intermingled with fibroblasts, vasculature, macrophages, mast cells and other cellular components. This composition is similar to another hallmark of NF1, which are the expansive growths within large nerves and plexuses referred to as plexiform neurofibromas (pNF). […] Although their histologic and genomic abnormalities are similar, the natural history of cNF and pNF is quite distinct. While pNF often present as congenital lesions, cNF are typically not present at birth. Instead, cNF usually begin to appear at puberty, accumulating thereafter to a variable degree over the remainder of the patients life.

• #51

  https://scite.ai/reports/10.1097/pap.0000000000000197

  Multiple cutaneous neurofibromas (cNF) are characteristic of neurofibromatosis type 1 (NF1) patients who have an autosomal dominant loss-of-function mutation of an NF1 allele. cNF are visibly protruding masses in the skin composed of a complex mixture of hyperproliferating Schwann cells (SC), particularly nonmyelinating SC (nSC), intermingled with fibroblasts, vasculature, macrophages, mast cells and other cellular components. This composition is similar to another hallmark of NF1, which are the expansive growths within large nerves and plexuses referred to as plexiform neurofibromas (pNF). […] Although their histologic and genomic abnormalities are similar, the natural history of cNF and pNF is quite distinct. While pNF often present as congenital lesions, cNF are typically not present at birth. Instead, cNF usually begin to appear at puberty, accumulating thereafter to a variable degree over the remainder of the patients life.

• #52

  https://scite.ai/reports/10.1097/pap.0000000000000197

  Multiple cutaneous neurofibromas (cNF) are characteristic of neurofibromatosis type 1 (NF1) patients who have an autosomal dominant loss-of-function mutation of an NF1 allele. cNF are visibly protruding masses in the skin composed of a complex mixture of hyperproliferating Schwann cells (SC), particularly nonmyelinating SC (nSC), intermingled with fibroblasts, vasculature, macrophages, mast cells and other cellular components. This composition is similar to another hallmark of NF1, which are the expansive growths within large nerves and plexuses referred to as plexiform neurofibromas (pNF). […] Although their histologic and genomic abnormalities are similar, the natural history of cNF and pNF is quite distinct. While pNF often present as congenital lesions, cNF are typically not present at birth. Instead, cNF usually begin to appear at puberty, accumulating thereafter to a variable degree over the remainder of the patients life.

• #53 Translating current basic research into future therapies for neurofibromatosis type 1 | British Journal of Cancer

  https://www.nature.com/articles/s41416-020-0903-x

  However, a pNF can progress into an atypical neurofibromatous neoplasm of uncertain biological potential (ANNUBP) typically as a result of a subsequent genetic mutation in CDKN2A and, upon further genetic insult to additional tumour-suppressor genes, such as TP53, PTEN or members of the PRC2 chromatin-remodelling complex, an ANNUBP or a pNF can transform into a MPNST. […] The lifetime risk of developing MPNSTs is 8-13% in all patients with NF1, although this risk is higher in patients with pNFs. […] NF1 patients can also develop OPGs. […] The microenvironment of OPGs is very heterogeneous and plays an essential role in tumorigenesis as in neurofibromas. […] Several studies have demonstrated that OPG tumour cell proliferation is largely dependent on the microglia, which secrete chemokine ligands to recruit more microglia and to induce the proliferation of astroglial tumour cells.

• #54 Translating current basic research into future therapies for neurofibromatosis type 1 | British Journal of Cancer

  https://www.nature.com/articles/s41416-020-0903-x

  However, a pNF can progress into an atypical neurofibromatous neoplasm of uncertain biological potential (ANNUBP) typically as a result of a subsequent genetic mutation in CDKN2A and, upon further genetic insult to additional tumour-suppressor genes, such as TP53, PTEN or members of the PRC2 chromatin-remodelling complex, an ANNUBP or a pNF can transform into a MPNST. […] The lifetime risk of developing MPNSTs is 8-13% in all patients with NF1, although this risk is higher in patients with pNFs. […] NF1 patients can also develop OPGs. […] The microenvironment of OPGs is very heterogeneous and plays an essential role in tumorigenesis as in neurofibromas. […] Several studies have demonstrated that OPG tumour cell proliferation is largely dependent on the microglia, which secrete chemokine ligands to recruit more microglia and to induce the proliferation of astroglial tumour cells.

• #55

  https://insight.jci.org/articles/view/136262

  Neurofibromatosis type 1 (NF1) is a rare genetic disorder, characterized by the development of benign and malignant nerve tumors. […] Although all individuals with NF1 harbor genetic alterations in the same gene, the clinical manifestations of NF1 are extremely heterogeneous even among individuals who carry identical genetic defects. […] In order to deepen the understanding of phenotypic manifestations in NF1, we comprehensively characterized the prevalence of 18 phenotypic traits in 2051 adults with NF1 from the Childrens Tumor Foundations NF1 registry. […] We further investigated the coassociation of traits and found positive correlations between spinal neurofibromas and pain, spinal neurofibromas and scoliosis, spinal neurofibromas and optic gliomas, and optic gliomas and sphenoid wing dysplasia.

• #56

  https://insight.jci.org/articles/view/136262

  Furthermore, with increasing numbers of cutaneous neurofibromas, the odds ratio of malignant peripheral nerve sheath tumor increased. […] Together, our results support potential shared molecular pathogenesis for certain clinical manifestations and illustrate the utility of disease registries for understanding rare diseases. […] Individuals with NF1 may have significant morbidity from the development of nervous system tumors, including neurofibromas, optic gliomas, and malignant nerve sheath tumors. […] Among individuals with NF1, the clinical manifestations are highly variable and unpredictable, even among individuals sharing identical genetic NF1 mutations, suggesting an influence of modifiers outside the NF1 locus. […] Understanding clinical trait associations and disease subtypes will ultimately pave the way for more informed and personalized disease management.

• #57 Neurofibromatosis 1 (von Recklinghausen Disease)

  https://www.jstage.jst.go.jp/article/kjm/advpub/0/advpub_2023-0013-IR/_html/-char/en

  Neurofibromatosis 1 (NF1), also known as von Recklinghausen disease, is one of the most common neurocutaneous genetic disorders. Loss of function of the NF1 gene results in overactivation of the RAS/MAPK pathway, leading to neurocutaneous manifestations and osseous abnormalities. […] NF1 is caused by heterozygous pathogenic variants in the NF1 gene on chromosome 17q11.2, resulting in RAS pathway activation. […] Although the pathogenesis of NF1-associated features has not been fully elucidated, loss of heterozygosity or biallelic inactivation of the NF1 gene in different cell lineages has been shown to be related to several manifestations. […] NF1 haploinsufficiency plays an important role in the development of neurofibromas. […] It is well known that NF1 acts as a tumor suppressor gene. Mutation of the NF1 gene increases signaling through the intracellular Ras/mitogen-activated protein kinase and phosphatidylinositol 3-kinase/AKT/mammalian target of the rapamycin (mTOR) pathway. […] In Japan, selumetinib was approved in 2022 for pediatric patients (aged 3-18 years) with symptomatic, inoperable PNF.

• #58 Rationale for haploinsufficiency correction therapy in neurofibromatosis type 1

  https://www.oaepublish.com/articles/jtgg.2022.14

  Neurofibromatosis type 1 (NF1) is a genetic disorder with a wide range of manifestations and severity. Currently, the few available NF1 treatments target specific manifestations, with no available therapies targeted to correct the underlying driver of all NF1 manifestations. Evidence supports that haploinsufficiency in NF1 caused by a decreased amount of wild-type (WT) neurofibromin in all NF1+/- cells directly causes or facilitates a range of NF1 manifestations. Consequently, NF1 haploinsufficiency correction therapy (NF1-HCT) represents a potentially effective approach to treat some NF1 manifestations. NF1-HCT would normalize the level of WT neurofibromin in all NF1-haploinsufficient cells, including those integral to the NF1 phenotype such as Schwann cells (SCs), melanocytes, neurons, bone cells, and cells of the tumor microenvironment. This would correct altered cellular signaling pathways and, in turn, restore normal function to cells with a retained WT allele. NF1-HCT will not restore WT neurofibromin in NF1-/- cells; however, by restoring function in the surrounding NF1+/- microenvironment cells, NF1-HCT is predicted to have a beneficial effect on NF1-/- cells. NF1-HCT is expected to have a clinical effect in some NF1 manifestations, as follows: (i) prevention, or delay of onset, of potential manifestations; and (ii) reversal, or halting/slowing progression, of established manifestations.

• #59 Rationale for haploinsufficiency correction therapy in neurofibromatosis type 1

  https://www.oaepublish.com/articles/jtgg.2022.14

  The abnormal cell function resulting from haploinsufficiency is critical in NF1 pathogenesis, with evidence supporting that it causes certain NF1 manifestations and permits or accelerates others. […] By normalizing the level of WT neurofibromin in all NF1-haploinsufficient cells, NF1-HCT is expected to normalize cell function and consequently reverse, prevent or delay the development of NF1 manifestations. […] The essential role of NF1-haploinsufficiency in the disease phenotype, whether acting singlehandedly or in concert with cLOF, makes NF1-HCT a promising strategy, with the potential to prevent, reverse or delay virtually all NF1 manifestations.

• #60 Rationale for haploinsufficiency correction therapy in neurofibromatosis type 1

  https://www.oaepublish.com/articles/jtgg.2022.14

  Neurofibromatosis type 1 (NF1) is a genetic disorder with a wide range of manifestations and severity. Currently, the few available NF1 treatments target specific manifestations, with no available therapies targeted to correct the underlying driver of all NF1 manifestations. Evidence supports that haploinsufficiency in NF1 caused by a decreased amount of wild-type (WT) neurofibromin in all NF1+/- cells directly causes or facilitates a range of NF1 manifestations. Consequently, NF1 haploinsufficiency correction therapy (NF1-HCT) represents a potentially effective approach to treat some NF1 manifestations. NF1-HCT would normalize the level of WT neurofibromin in all NF1-haploinsufficient cells, including those integral to the NF1 phenotype such as Schwann cells (SCs), melanocytes, neurons, bone cells, and cells of the tumor microenvironment. This would correct altered cellular signaling pathways and, in turn, restore normal function to cells with a retained WT allele. NF1-HCT will not restore WT neurofibromin in NF1-/- cells; however, by restoring function in the surrounding NF1+/- microenvironment cells, NF1-HCT is predicted to have a beneficial effect on NF1-/- cells. NF1-HCT is expected to have a clinical effect in some NF1 manifestations, as follows: (i) prevention, or delay of onset, of potential manifestations; and (ii) reversal, or halting/slowing progression, of established manifestations.

• #61 Rationale for haploinsufficiency correction therapy in neurofibromatosis type 1

  https://www.oaepublish.com/articles/jtgg.2022.14

  Neurofibromatosis type 1 (NF1) is a genetic disorder with a wide range of manifestations and severity. Currently, the few available NF1 treatments target specific manifestations, with no available therapies targeted to correct the underlying driver of all NF1 manifestations. Evidence supports that haploinsufficiency in NF1 caused by a decreased amount of wild-type (WT) neurofibromin in all NF1+/- cells directly causes or facilitates a range of NF1 manifestations. Consequently, NF1 haploinsufficiency correction therapy (NF1-HCT) represents a potentially effective approach to treat some NF1 manifestations. NF1-HCT would normalize the level of WT neurofibromin in all NF1-haploinsufficient cells, including those integral to the NF1 phenotype such as Schwann cells (SCs), melanocytes, neurons, bone cells, and cells of the tumor microenvironment. This would correct altered cellular signaling pathways and, in turn, restore normal function to cells with a retained WT allele. NF1-HCT will not restore WT neurofibromin in NF1-/- cells; however, by restoring function in the surrounding NF1+/- microenvironment cells, NF1-HCT is predicted to have a beneficial effect on NF1-/- cells. NF1-HCT is expected to have a clinical effect in some NF1 manifestations, as follows: (i) prevention, or delay of onset, of potential manifestations; and (ii) reversal, or halting/slowing progression, of established manifestations.

• #62 Rationale for haploinsufficiency correction therapy in neurofibromatosis type 1

  https://www.oaepublish.com/articles/jtgg.2022.14

  Neurofibromatosis type 1 (NF1) is a genetic disorder with a wide range of manifestations and severity. Currently, the few available NF1 treatments target specific manifestations, with no available therapies targeted to correct the underlying driver of all NF1 manifestations. Evidence supports that haploinsufficiency in NF1 caused by a decreased amount of wild-type (WT) neurofibromin in all NF1+/- cells directly causes or facilitates a range of NF1 manifestations. Consequently, NF1 haploinsufficiency correction therapy (NF1-HCT) represents a potentially effective approach to treat some NF1 manifestations. NF1-HCT would normalize the level of WT neurofibromin in all NF1-haploinsufficient cells, including those integral to the NF1 phenotype such as Schwann cells (SCs), melanocytes, neurons, bone cells, and cells of the tumor microenvironment. This would correct altered cellular signaling pathways and, in turn, restore normal function to cells with a retained WT allele. NF1-HCT will not restore WT neurofibromin in NF1-/- cells; however, by restoring function in the surrounding NF1+/- microenvironment cells, NF1-HCT is predicted to have a beneficial effect on NF1-/- cells. NF1-HCT is expected to have a clinical effect in some NF1 manifestations, as follows: (i) prevention, or delay of onset, of potential manifestations; and (ii) reversal, or halting/slowing progression, of established manifestations.

• #63 Rationale for haploinsufficiency correction therapy in neurofibromatosis type 1

  https://www.oaepublish.com/articles/jtgg.2022.14

  Neurofibromatosis type 1 (NF1) is a genetic disorder with a wide range of manifestations and severity. Currently, the few available NF1 treatments target specific manifestations, with no available therapies targeted to correct the underlying driver of all NF1 manifestations. Evidence supports that haploinsufficiency in NF1 caused by a decreased amount of wild-type (WT) neurofibromin in all NF1+/- cells directly causes or facilitates a range of NF1 manifestations. Consequently, NF1 haploinsufficiency correction therapy (NF1-HCT) represents a potentially effective approach to treat some NF1 manifestations. NF1-HCT would normalize the level of WT neurofibromin in all NF1-haploinsufficient cells, including those integral to the NF1 phenotype such as Schwann cells (SCs), melanocytes, neurons, bone cells, and cells of the tumor microenvironment. This would correct altered cellular signaling pathways and, in turn, restore normal function to cells with a retained WT allele. NF1-HCT will not restore WT neurofibromin in NF1-/- cells; however, by restoring function in the surrounding NF1+/- microenvironment cells, NF1-HCT is predicted to have a beneficial effect on NF1-/- cells. NF1-HCT is expected to have a clinical effect in some NF1 manifestations, as follows: (i) prevention, or delay of onset, of potential manifestations; and (ii) reversal, or halting/slowing progression, of established manifestations.

• #64 Rationale for haploinsufficiency correction therapy in neurofibromatosis type 1

  https://www.oaepublish.com/articles/jtgg.2022.14

  Neurofibromatosis type 1 (NF1) is a genetic disorder with a wide range of manifestations and severity. Currently, the few available NF1 treatments target specific manifestations, with no available therapies targeted to correct the underlying driver of all NF1 manifestations. Evidence supports that haploinsufficiency in NF1 caused by a decreased amount of wild-type (WT) neurofibromin in all NF1+/- cells directly causes or facilitates a range of NF1 manifestations. Consequently, NF1 haploinsufficiency correction therapy (NF1-HCT) represents a potentially effective approach to treat some NF1 manifestations. NF1-HCT would normalize the level of WT neurofibromin in all NF1-haploinsufficient cells, including those integral to the NF1 phenotype such as Schwann cells (SCs), melanocytes, neurons, bone cells, and cells of the tumor microenvironment. This would correct altered cellular signaling pathways and, in turn, restore normal function to cells with a retained WT allele. NF1-HCT will not restore WT neurofibromin in NF1-/- cells; however, by restoring function in the surrounding NF1+/- microenvironment cells, NF1-HCT is predicted to have a beneficial effect on NF1-/- cells. NF1-HCT is expected to have a clinical effect in some NF1 manifestations, as follows: (i) prevention, or delay of onset, of potential manifestations; and (ii) reversal, or halting/slowing progression, of established manifestations.

• #65 Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1 | Nature

  https://www.nature.com/articles/nature711

  Neurofibromatosis type I (NF1) is one of the most common single-gene disorders that causes learning deficits in humans. […] Mice carrying a heterozygous null mutation of the Nf1 gene (Nf1+/) show important features of the learning deficits associated with NF1. […] Here we show that the learning deficits of Nf1+/ mice can be rescued by genetic and pharmacological manipulations that decrease Ras function. […] Our results indicate that the learning deficits associated with NF1 may be caused by excessive Ras activity, which leads to impairments in long-term potentiation caused by increased GABA-mediated inhibition. […] Our findings have implications for the development of treatments for learning deficits associated with NF1.

• #66

  https://insight.jci.org/articles/view/136262

  Neurofibromatosis type 1 (NF1) is a rare genetic disorder, characterized by the development of benign and malignant nerve tumors. […] Although all individuals with NF1 harbor genetic alterations in the same gene, the clinical manifestations of NF1 are extremely heterogeneous even among individuals who carry identical genetic defects. […] In order to deepen the understanding of phenotypic manifestations in NF1, we comprehensively characterized the prevalence of 18 phenotypic traits in 2051 adults with NF1 from the Childrens Tumor Foundations NF1 registry. […] We further investigated the coassociation of traits and found positive correlations between spinal neurofibromas and pain, spinal neurofibromas and scoliosis, spinal neurofibromas and optic gliomas, and optic gliomas and sphenoid wing dysplasia.

• #67

  https://insight.jci.org/articles/view/136262

  Furthermore, with increasing numbers of cutaneous neurofibromas, the odds ratio of malignant peripheral nerve sheath tumor increased. […] Together, our results support potential shared molecular pathogenesis for certain clinical manifestations and illustrate the utility of disease registries for understanding rare diseases. […] Individuals with NF1 may have significant morbidity from the development of nervous system tumors, including neurofibromas, optic gliomas, and malignant nerve sheath tumors. […] Among individuals with NF1, the clinical manifestations are highly variable and unpredictable, even among individuals sharing identical genetic NF1 mutations, suggesting an influence of modifiers outside the NF1 locus. […] Understanding clinical trait associations and disease subtypes will ultimately pave the way for more informed and personalized disease management.

• #68 Neurofibromin – Wikipedia

  https://en.wikipedia.org/wiki/Neurofibromin

  NF1 has one of the highest mutation rates amongst known human genes, however mutation detection is difficult because of its large size, the presence of pseudogenes, and the variety of possible mutations. The NF1 locus has a high incidence of de novo mutations, meaning that the mutations are not inherited maternally or paternally. Although the mutation rate is high, there are no mutation „hot spot” regions. Mutations tend to be distributed within the gene, although exons 3, 5, and 27 are common sites for mutations. […] Through its NF1-GRD domain, neurofibromin increases the rate of GTP hydrolysis of Ras, and acts as a tumor suppressor by reducing Ras activity. When the Ras-Nf1 complex assembles, active Ras binds in a groove that is present in the neurofibromin catalytic domain. This binding occurs through Ras switch regions I and II, and an arginine finger present in neurofibromin. The interaction between Ras and neurofibromin causes GAP-stimulated hydrolysis of GTP to GDP. This process depends on the stabilization of residues in the Ras switch I and switch II regions, which drives Ras into the confirmation required for enzymatic function. This interaction between Ras and neurofibromin also requires the transition state of GDP hydrolysis to be stabilized, which is performed through the insertion of the positively charged arginine finger into the Ras active site. This neutralizes the negative charges that are present on GTP during phosphoryl transfer. By hydrolyzing GTP to GDP, neurofibromin inactivates Ras and therefore negatively regulates the Ras pathway, which controls the expression of genes involved in apoptosis, the cell cycle, cell differentiation or migration.

• #69 Translating current basic research into future therapies for neurofibromatosis type 1 | British Journal of Cancer

  https://www.nature.com/articles/s41416-020-0903-x

  The NF1 gene encodes neurofibromin, a GTPase-activating protein (GAP) that negatively regulates the oncoprotein RAS. […] The penetrance is almost 100%, but the expressivity varies greatly, even between twins. […] This observation has given rise to the spatiotemporal hypothesis, which proposes that, in addition to the nature of the NF1 mutation and additional genetic/epigenetic differences, the timing and the exact cell population that is undergoing loss of the second functional copy of NF1 are key factors that explain the overall phenotype. […] Tumorigenesis is a multi-step process that progressively transforms a normal tissue into a benign one (e.g. cNF, pNF, OPG) and potentially subsequently into a malignant one (e.g. MPNST). […] In the context of NF1-related tumours, it is unclear whether all NF1-associated MPNSTs originate from a pre-existing pNF.

• #70 Translating current basic research into future therapies for neurofibromatosis type 1 | British Journal of Cancer

  https://www.nature.com/articles/s41416-020-0903-x

  The NF1 gene encodes neurofibromin, a GTPase-activating protein (GAP) that negatively regulates the oncoprotein RAS. […] The penetrance is almost 100%, but the expressivity varies greatly, even between twins. […] This observation has given rise to the spatiotemporal hypothesis, which proposes that, in addition to the nature of the NF1 mutation and additional genetic/epigenetic differences, the timing and the exact cell population that is undergoing loss of the second functional copy of NF1 are key factors that explain the overall phenotype. […] Tumorigenesis is a multi-step process that progressively transforms a normal tissue into a benign one (e.g. cNF, pNF, OPG) and potentially subsequently into a malignant one (e.g. MPNST). […] In the context of NF1-related tumours, it is unclear whether all NF1-associated MPNSTs originate from a pre-existing pNF.

• #71

  https://insight.jci.org/articles/view/136262

  Previous studies have found coassociation of phenotypic traits in NF1, such as plexiform neurofibromas and MPNST, suggesting that multiple phenotypes may share common molecular pathways. […] Interestingly, we found optic gliomas were positively associated with sphenoid wing dysplasia. […] This suggests that phenotypic modifiers occur outside the NF1 locus, and further genetic studies are required to understand these modifiers. […] The strong overlap of these described phenotypes associated with genetic alterations highlights the potential impact of genetic variants both in NF1 and outside loci in modifying NF1 traits and influencing disease subtypes.

• #72

  https://insight.jci.org/articles/view/136262

  Previous studies have found coassociation of phenotypic traits in NF1, such as plexiform neurofibromas and MPNST, suggesting that multiple phenotypes may share common molecular pathways. […] Interestingly, we found optic gliomas were positively associated with sphenoid wing dysplasia. […] This suggests that phenotypic modifiers occur outside the NF1 locus, and further genetic studies are required to understand these modifiers. […] The strong overlap of these described phenotypes associated with genetic alterations highlights the potential impact of genetic variants both in NF1 and outside loci in modifying NF1 traits and influencing disease subtypes.

• #73

  https://insight.jci.org/articles/view/136262

  Previous studies have found coassociation of phenotypic traits in NF1, such as plexiform neurofibromas and MPNST, suggesting that multiple phenotypes may share common molecular pathways. […] Interestingly, we found optic gliomas were positively associated with sphenoid wing dysplasia. […] This suggests that phenotypic modifiers occur outside the NF1 locus, and further genetic studies are required to understand these modifiers. […] The strong overlap of these described phenotypes associated with genetic alterations highlights the potential impact of genetic variants both in NF1 and outside loci in modifying NF1 traits and influencing disease subtypes.

• #74 Translating current basic research into future therapies for neurofibromatosis type 1 | British Journal of Cancer

  https://www.nature.com/articles/s41416-020-0903-x

  Recent advances in our understanding of tumour molecular and cellular pathogenesis will provide opportunities to develop effective treatments in the future for NF1-associated neoplasms. […] The Hippo pathway acts as a modifier and a driver, respectively, suggesting that selectively dampening the Hippo pathway using inhibitors could be an attractive therapeutic approach. […] Signalling through the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is known to contribute to tumorigenesis in numerous ways. […] In brief, interfering with the STAT3 pathway delayed neurofibroma initiation as well as progression to MPNST, but had far less impact on tumour maintenance. […] The existence of mouse models in the NF1 arena has provided unprecedented opportunities to derive important insights into the biology of the disease as well as preclinical models that guide the development of effective therapies for NF1.

• #75 Neurofibromatosis 1 (von Recklinghausen Disease)

  https://www.jstage.jst.go.jp/article/kjm/advpub/0/advpub_2023-0013-IR/_html/-char/en

  Neurofibromatosis 1 (NF1), also known as von Recklinghausen disease, is one of the most common neurocutaneous genetic disorders. Loss of function of the NF1 gene results in overactivation of the RAS/MAPK pathway, leading to neurocutaneous manifestations and osseous abnormalities. […] NF1 is caused by heterozygous pathogenic variants in the NF1 gene on chromosome 17q11.2, resulting in RAS pathway activation. […] Although the pathogenesis of NF1-associated features has not been fully elucidated, loss of heterozygosity or biallelic inactivation of the NF1 gene in different cell lineages has been shown to be related to several manifestations. […] NF1 haploinsufficiency plays an important role in the development of neurofibromas. […] It is well known that NF1 acts as a tumor suppressor gene. Mutation of the NF1 gene increases signaling through the intracellular Ras/mitogen-activated protein kinase and phosphatidylinositol 3-kinase/AKT/mammalian target of the rapamycin (mTOR) pathway. […] In Japan, selumetinib was approved in 2022 for pediatric patients (aged 3-18 years) with symptomatic, inoperable PNF.

• #76 Neurofibromatosis: Type 1 | PM&R KnowledgeNow

  https://now.aapmr.org/neurofibromatosis-type-1/

  NF1 is a genetic disorder resulting from a mutation in the NF1 tumor suppressor gene located at chromosome 17q11.2, which encodes the guanosine triphosphatase-activating protein neurofibromin. Decreased production of neurofibromin results in the overactivation of the RAS pathway involved in promoting cell growth/division. […] The mechanism is thought to be multifactorial, from secondary pain from tumors to changes in pain pathways. […] The signaling pathways controlled by neurofibromin protein are better understood, and biological targets have been identified with potential for treatment of the tumors. Targeted inhibition of the RAS pathway via mitogen-activated protein kinase (MEK) inhibition has been successful. Specifically, the oral biologic, selumetinib, has been shown to slow the progression of growth of plexiform neurofibromas and improve pain and overall function.

• #77 Neurofibromatosis Type 1 and tumorigenesis: molecular mechanisms and therapeutic implications in: Neurosurgical Focus Volume 28 Issue 1 (2010) Journals

  https://thejns.org/focus/view/journals/neurosurg-focus/28/1/article-pE8.xml

  Importantly, a complex series of interactions with these other cell types in neurofibroma tumorigenesis is mediated by abnormal expression of growth factors and their receptors and modification of gene expression, a key example of which is the process of recruitment and involvement of the NF1+/ heterozygous mast cell. […] In general, for malignant transformation to occur, there must be accumulation of additional mutations of multiple genes including INK4A/ARF and P53, with resulting abnormalities of their respective signal cascades. […] Further, abnormalities of the NF1 gene and molecular cascade described above have been implicated in the tumorigenesis of NF1 and some sporadically occurring gliomas, and thus, these treatment options may have wider applicability. […] Finally, increased knowledge of molecular and cellular mechanisms involved with NF1 tumorigenesis has led to multiple preclinical and clinical studies of targeted therapy, including the mTOR inhibitor rapamycin, which is demonstrating promising preclinical results for treatment of MPNSTs and gliomas.

• #78 Translating current basic research into future therapies for neurofibromatosis type 1 | British Journal of Cancer

  https://www.nature.com/articles/s41416-020-0903-x

  Recent advances in our understanding of tumour molecular and cellular pathogenesis will provide opportunities to develop effective treatments in the future for NF1-associated neoplasms. […] The Hippo pathway acts as a modifier and a driver, respectively, suggesting that selectively dampening the Hippo pathway using inhibitors could be an attractive therapeutic approach. […] Signalling through the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is known to contribute to tumorigenesis in numerous ways. […] In brief, interfering with the STAT3 pathway delayed neurofibroma initiation as well as progression to MPNST, but had far less impact on tumour maintenance. […] The existence of mouse models in the NF1 arena has provided unprecedented opportunities to derive important insights into the biology of the disease as well as preclinical models that guide the development of effective therapies for NF1.

• #79 Translating current basic research into future therapies for neurofibromatosis type 1 | British Journal of Cancer

  https://www.nature.com/articles/s41416-020-0903-x

  Recent advances in our understanding of tumour molecular and cellular pathogenesis will provide opportunities to develop effective treatments in the future for NF1-associated neoplasms. […] The Hippo pathway acts as a modifier and a driver, respectively, suggesting that selectively dampening the Hippo pathway using inhibitors could be an attractive therapeutic approach. […] Signalling through the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is known to contribute to tumorigenesis in numerous ways. […] In brief, interfering with the STAT3 pathway delayed neurofibroma initiation as well as progression to MPNST, but had far less impact on tumour maintenance. […] The existence of mouse models in the NF1 arena has provided unprecedented opportunities to derive important insights into the biology of the disease as well as preclinical models that guide the development of effective therapies for NF1.

• #80 Immune system changes in the pathogenesis of neurofibromatosis type 1

  https://ouci.dntb.gov.ua/en/works/7pbq8PBl/

  Neurofibromatosis type 1 (NF1) is caused by germline heterozygous mutations in the NF1 gene, which encodes the oncosuppressor neurofibromin. […] The deficiency of neurofibromin impairs the differentiation and correct functioning of immune system cells. […] The development of neurofibromas is associated with the fact that NF1–/– Schwann cells stimulate the migration of mast cells into the tumor microenvironment, which actively degranulate. […] Therefore, in the treatment of NF1, the use of ketotifen and a kit/fms kinase inhibitor is recommended. […] Macrophages and T-lymphocytes in neurofibromas do not provide an antitumor response, but promote inflammation and tumor growth. […] Therefore, a promising direction is NF1 therapy with STAT3 inhibitors and immune checkpoint inhibitors that block programmed cell death ligand 1 (PD-L1).

• #81 Immune system changes in the pathogenesis of neurofibromatosis type 1

  https://ouci.dntb.gov.ua/en/works/7pbq8PBl/

  Activation of MEK signaling pathways in NF1 leads to PD-L1 stimulation; therefore, MEK inhibitors, which also suppress the RAS/RAF/MEK/ERK system, turned out to be effective in the treatment of NF1. […] For the treatment of sporadic malignant neoplasms, in the development of which NF1 mutations play a role, the developed methods of NF1 therapy can be used.

• #82 Rationale for haploinsufficiency correction therapy in neurofibromatosis type 1

  https://www.oaepublish.com/articles/jtgg.2022.14

  Neurofibromatosis type 1 (NF1) is a genetic disorder with a wide range of manifestations and severity. Currently, the few available NF1 treatments target specific manifestations, with no available therapies targeted to correct the underlying driver of all NF1 manifestations. Evidence supports that haploinsufficiency in NF1 caused by a decreased amount of wild-type (WT) neurofibromin in all NF1+/- cells directly causes or facilitates a range of NF1 manifestations. Consequently, NF1 haploinsufficiency correction therapy (NF1-HCT) represents a potentially effective approach to treat some NF1 manifestations. NF1-HCT would normalize the level of WT neurofibromin in all NF1-haploinsufficient cells, including those integral to the NF1 phenotype such as Schwann cells (SCs), melanocytes, neurons, bone cells, and cells of the tumor microenvironment. This would correct altered cellular signaling pathways and, in turn, restore normal function to cells with a retained WT allele. NF1-HCT will not restore WT neurofibromin in NF1-/- cells; however, by restoring function in the surrounding NF1+/- microenvironment cells, NF1-HCT is predicted to have a beneficial effect on NF1-/- cells. NF1-HCT is expected to have a clinical effect in some NF1 manifestations, as follows: (i) prevention, or delay of onset, of potential manifestations; and (ii) reversal, or halting/slowing progression, of established manifestations.

• #83 Rationale for haploinsufficiency correction therapy in neurofibromatosis type 1

  https://www.oaepublish.com/articles/jtgg.2022.14

  Neurofibromatosis type 1 (NF1) is a genetic disorder with a wide range of manifestations and severity. Currently, the few available NF1 treatments target specific manifestations, with no available therapies targeted to correct the underlying driver of all NF1 manifestations. Evidence supports that haploinsufficiency in NF1 caused by a decreased amount of wild-type (WT) neurofibromin in all NF1+/- cells directly causes or facilitates a range of NF1 manifestations. Consequently, NF1 haploinsufficiency correction therapy (NF1-HCT) represents a potentially effective approach to treat some NF1 manifestations. NF1-HCT would normalize the level of WT neurofibromin in all NF1-haploinsufficient cells, including those integral to the NF1 phenotype such as Schwann cells (SCs), melanocytes, neurons, bone cells, and cells of the tumor microenvironment. This would correct altered cellular signaling pathways and, in turn, restore normal function to cells with a retained WT allele. NF1-HCT will not restore WT neurofibromin in NF1-/- cells; however, by restoring function in the surrounding NF1+/- microenvironment cells, NF1-HCT is predicted to have a beneficial effect on NF1-/- cells. NF1-HCT is expected to have a clinical effect in some NF1 manifestations, as follows: (i) prevention, or delay of onset, of potential manifestations; and (ii) reversal, or halting/slowing progression, of established manifestations.

• #84 Rationale for haploinsufficiency correction therapy in neurofibromatosis type 1

  https://www.oaepublish.com/articles/jtgg.2022.14

  Neurofibromatosis type 1 (NF1) is a genetic disorder with a wide range of manifestations and severity. Currently, the few available NF1 treatments target specific manifestations, with no available therapies targeted to correct the underlying driver of all NF1 manifestations. Evidence supports that haploinsufficiency in NF1 caused by a decreased amount of wild-type (WT) neurofibromin in all NF1+/- cells directly causes or facilitates a range of NF1 manifestations. Consequently, NF1 haploinsufficiency correction therapy (NF1-HCT) represents a potentially effective approach to treat some NF1 manifestations. NF1-HCT would normalize the level of WT neurofibromin in all NF1-haploinsufficient cells, including those integral to the NF1 phenotype such as Schwann cells (SCs), melanocytes, neurons, bone cells, and cells of the tumor microenvironment. This would correct altered cellular signaling pathways and, in turn, restore normal function to cells with a retained WT allele. NF1-HCT will not restore WT neurofibromin in NF1-/- cells; however, by restoring function in the surrounding NF1+/- microenvironment cells, NF1-HCT is predicted to have a beneficial effect on NF1-/- cells. NF1-HCT is expected to have a clinical effect in some NF1 manifestations, as follows: (i) prevention, or delay of onset, of potential manifestations; and (ii) reversal, or halting/slowing progression, of established manifestations.

• #85 Rationale for haploinsufficiency correction therapy in neurofibromatosis type 1

  https://www.oaepublish.com/articles/jtgg.2022.14

  Neurofibromatosis type 1 (NF1) is a genetic disorder with a wide range of manifestations and severity. Currently, the few available NF1 treatments target specific manifestations, with no available therapies targeted to correct the underlying driver of all NF1 manifestations. Evidence supports that haploinsufficiency in NF1 caused by a decreased amount of wild-type (WT) neurofibromin in all NF1+/- cells directly causes or facilitates a range of NF1 manifestations. Consequently, NF1 haploinsufficiency correction therapy (NF1-HCT) represents a potentially effective approach to treat some NF1 manifestations. NF1-HCT would normalize the level of WT neurofibromin in all NF1-haploinsufficient cells, including those integral to the NF1 phenotype such as Schwann cells (SCs), melanocytes, neurons, bone cells, and cells of the tumor microenvironment. This would correct altered cellular signaling pathways and, in turn, restore normal function to cells with a retained WT allele. NF1-HCT will not restore WT neurofibromin in NF1-/- cells; however, by restoring function in the surrounding NF1+/- microenvironment cells, NF1-HCT is predicted to have a beneficial effect on NF1-/- cells. NF1-HCT is expected to have a clinical effect in some NF1 manifestations, as follows: (i) prevention, or delay of onset, of potential manifestations; and (ii) reversal, or halting/slowing progression, of established manifestations.

• #86 Rationale for haploinsufficiency correction therapy in neurofibromatosis type 1

  https://www.oaepublish.com/articles/jtgg.2022.14

  The abnormal cell function resulting from haploinsufficiency is critical in NF1 pathogenesis, with evidence supporting that it causes certain NF1 manifestations and permits or accelerates others. […] By normalizing the level of WT neurofibromin in all NF1-haploinsufficient cells, NF1-HCT is expected to normalize cell function and consequently reverse, prevent or delay the development of NF1 manifestations. […] The essential role of NF1-haploinsufficiency in the disease phenotype, whether acting singlehandedly or in concert with cLOF, makes NF1-HCT a promising strategy, with the potential to prevent, reverse or delay virtually all NF1 manifestations.

• #87 Neurofibromatosis type 1-associated optic pathway gliomas: pathogenesis and emerging treatments

  https://www.europeanreview.org/article/32804

  Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder associated with an increased risk of developing a variety of benign and malignant tumors. […] Over the past decade, basic research and the development of genetically engineered mice models of NF1-associated OPG have shed light on the cellular and molecular mechanisms underlying the disease and inspired animal and human testing of several compounds. A promising line of research is focusing on the inhibition of mTOR, a protein kinase controlling proliferation, protein synthesis rate and cell motility that is highly expressed in neoplastic cells. […] A different strategy aims at restoring cAMP levels in neoplastic astrocytes and non-neoplastic neurons, since reduced intracellular cAMP levels contribute to OPG growth and, more importantly, are the major determinant of NF1-OPG-associated visual decline.

• #88 Neurofibromatosis Type 1 (NF1) – Le Lab

  https://med.virginia.edu/le-lab/research/neurofibromatosis-type-1/

  Neurofibromatosis Type 1 (NF1) is caused by mutations in the NF1 tumor suppressor gene, which encodes a GTPase activating protein (GAP) that negatively regulates p21-RAS signaling. […] Recent work has demonstrated a critical role for the tumor microenvironment in neurofibroma genesis. […] Therefore, a better understanding of the molecular mechanisms underlying neurofibroma development, as well as the interaction of the tumor cells with the cells in the microenvironment will provide a foothold to develop new therapies aimed at delaying or preventing tumor formation in NF1 patients. […] The Le Lab is investigating how early, initiating genetic events such as loss of NF1 interplay with microenvironmental factors to regulate tumorigenesis. […] These studies have also provided important insights into the molecular and cellular pathogenesis of NF and have served as a foothold for development of novel therapies for preventing or delaying tumor formation in NF patients.

• #89

  https://www.jci.org/articles/view/139807

  The studies presented here address this pressing need through the generation of robust hiPSC-derived neurofibroma and cNF mouse models. […] Using these systems, we discovered that NF1 loss impaired Schwann cell lineage differentiation by maintaining a more stem-like state, which likely facilitated tumorigenesis. […] Taken together, the generation and authentication of these neurofibroma models establishes tractable platforms for future preclinical therapeutic discovery and testing.

• #90 Neurofibroma Development in Neurofibromatosis Type 1: Insights from Cellular Origin and Schwann Cell Lineage Development—-Shanghai Institute of Nutrition and Health,Chinese Academy of Sciences

  https://english.sinh.cas.cn/research/papers/202503/t20250319_907460.html

  The distinct spatiotemporal characteristics of plexiform and cutaneous neurofibromas have prompted hypotheses about the origin and developmental features of these tumors, involving various cellular transition processes. […] We highlighted the Schwann cell (SC) lineage shift to better present the evolution of its corresponding cellular origin hypothesis and its important effects on the progression and malignant transformation of neurofibromas. […] By integrating findings relating to tumor formation, growth, and malignancy, we hope to reveal the role of SC lineage shift as well as the combined impact of additional determinants in the natural history of PNSTs.

• #91 Neurofibromatosis type 1-associated optic pathway gliomas: pathogenesis and emerging treatments

  https://www.europeanreview.org/article/32804

  The importance of NF1-mutant RGCs in the formation and progression of OPGs also holds promise for clinical translation. […] The growing understanding of the unique cellular and molecular characteristics of NF1-OPG, coupled with the recent publication of promising clinical studies, raise hope for a shift towards precision medicine and targeted therapies as a first-line treatment.

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