Materiały źródłowe

• #1 Neurofibromatosis Type 2 – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK470350/

  Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder characterized by the development of multiple tumors involving the central nervous system (CNS). […] NF2 is caused by mutations in the NF2 gene located in the long arm of chromosome number 22 (22q12.2). The NF2 gene encodes for the protein known as merlin, which acts as a tumor suppressor gene. […] Bilateral vestibular schwannomas are the hallmark feature of NF2 and are present in approximately 90% to 95% of patients. Meningiomas are seen in approximately 50% of patients with NF2.

• #2 Neurofibromatosis type 2

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4748851/

  Neurofibromatosis type 2 is an autosomal-dominant multiple neoplasia syndrome that results from mutations in the NF2 tumour suppressor gene located on chromosome 22q. […] The NF2 tumour suppressor gene was identified in 1993. It has 17 exons that encode for a 69 kDa protein product called merlin (moesin-ezrin-radixin-like protein) or schwannomin. […] Consistent with Knudsons two-hit hypothesis of tumorigenesis, tumour formation initiates when both alleles of this gene are inactivated. […] Somatic inactivation of both alleles of this gene happens in sporadic schwannomas (90%), meningiomas (50%), and ependymomas (5%). […] Abnormal or absent merlin function (as in neurofibromatosis type 2) can disrupt tumour suppression via various mechanisms, but the importance of merlins many protein interactions in this process has not been fully elucidated.

• #3 NF2-related schwannomatosis (NF2-SWN; formerly neurofibromatosis type 2) – UpToDate

  https://www.uptodate.com/contents/nf2-related-schwannomatosis-nf2-swn-formerly-neurofibromatosis-type-2/print

  NF2-related schwannomatosis (NF2-SWN; formerly neurofibromatosis type 2) is an autosomal dominantly inherited syndrome that predisposes individuals to bilateral vestibular schwannomas as well as multiple other tumors of the nervous system. NF2-SWN is caused by pathogenic variants in the NF2, moesin-ezrin-radixin like (MERLIN) tumor suppressor (NF2) gene, which produces merlin, a tumor suppressor. […] The molecular pathogenesis, clinical features, diagnosis, and management of NF2-SWN are reviewed here.

• #4 Neurofibromatosis type II – Wikipedia

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

  Neurofibromatosis type II (NF2) is caused by mutations of the „Merlin” gene, which seems to influence the form and movement of cells. […] NF2 is caused by a defect in the gene that normally gives rise to a product called Merlin or Schwannomin, located on chromosome 22 band q11-13.1. Merlin was first discovered as a structural protein functioning as an actin cytoskeleton regulator. Later merlin’s tumour suppressant role was described. Merlin regulates multiple proliferative signalling cascades such as receptor tyrosine kinase signalling, p21-activated kinase signalling, Ras signalling, MEK-ERK cascade, MST-YAP cascade. […] It has been shown that Merlin inhibits Rac1 which is crucial for cell motility and tumour invasion. […] It is known that Merlin’s deficiency can result in unmediated progression through the cell cycle due to the lack of contact-mediated tumour suppression, mainly because of the cell:cell junction disruption, sufficient to result in the tumors characteristic of Neurofibromatosis type II.

• #5 Neurofibromatosis Type 2 (NF2) and the Implications for Vestibular Schwannoma and Meningioma Pathogenesis

  https://www.mdpi.com/1422-0067/22/2/690

  Patients diagnosed with neurofibromatosis type 2 (NF2) are extremely likely to develop meningiomas, in addition to vestibular schwannomas. […] In NF2, patients have mutations in the NF2 gene, specifically with loss of function in a tumor-suppressor protein that has a number of synonymous names, including: Merlin, Neurofibromin 2, and schwannomin. […] The Hippo Tumor Suppressor pathway is regulated upstream by Merlin. This pathway is critical in regulating cell proliferation and apoptosis, characteristics that are important for tumor progression. […] Mutations of the NF2 gene are strongly associated with NF2 diagnosis, leading to benign proliferative conditions such as vestibular schwannomas and meningiomas. […] Loss of chromosome 22 has been widely implicated in the pathogenesis of meningioma, sharing a common pathway for tumorigenesis with NF2 patients due to the presence of neurofibromin on chromosome 22q12.2.

• #6 Neurofibromatosis type 2 (NF2): A clinical and molecular review | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-4-16

  Neurofibromatosis type 2 (NF2) is a dominantly inherited tumour predisposition syndrome caused by mutations in the NF2 gene on chromosome 22. […] NF2 is a genetically homogeneous condition, with no evidence for another genetic cause of classical NF2 (bilateral VS). […] Seizinger et al. were the first to show loss of constitutional heterozygosity of chromosome 22, with DNA markers lost in tumours from a patient with NF2. […] The NF2 gene was then isolated by the simultaneous discovery of constitutional and tumour deletions in a gene coding for a cell membrane-related protein, which has been termed merlin or schwannomin by the two groups who isolated it. […] Standard mutation techniques, such as Single Strand Conformational Polymorphism (SSCP) analysis or Denaturing Gradient Gel Electrophoresis, detected between 35% and 66% of pathogenic mutations.

• #7 NF2-related schwannomatosis (NF2-SWN; formerly neurofibromatosis type 2) – UpToDate

  https://www.uptodate.com/contents/nf2-related-schwannomatosis-nf2-swn-formerly-neurofibromatosis-type-2/print

  NF2-related schwannomatosis (NF2-SWN; formerly neurofibromatosis type 2) is an autosomal dominantly inherited syndrome that predisposes individuals to bilateral vestibular schwannomas as well as multiple other tumors of the nervous system. NF2-SWN is caused by pathogenic variants in the NF2, moesin-ezrin-radixin like (MERLIN) tumor suppressor (NF2) gene, which produces merlin, a tumor suppressor. […] The molecular pathogenesis, clinical features, diagnosis, and management of NF2-SWN are reviewed here.

• #8 Neurofibromatosis – Wikipedia

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

  Neurofibromatosis type II is caused by a mutation on chromosome 22 (22q12). The mutation falls on the NF2 tumor suppressor gene. The gene normally encodes a cytoplasmic protein known as merlin. The normal function of merlin is to regulate the activity of multiple growth factors, the mutated copy of the gene leads to merlin’s loss of function. The loss of function leads to increased activity of growth factors normally regulated by merlin, leading to the formation of the tumors associated with NF2. […] The pathophysiology is varied, and each NF type has a different one: […] Neurofibromatosis type II is caused by a mutation on chromosome 22 (22q12). The mutation falls on the NF2 tumor suppressor gene. The gene normally encodes a cytoplasmic protein known as merlin. The normal function of merlin is to regulate the activity of multiple growth factors, the mutated copy of the gene leads to merlin’s loss of function. The loss of function leads to increased activity of growth factors normally regulated by merlin, leading to the formation of the tumors associated with NF2.

• #9 Neurofibromatosis Type 2 – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK470350/

  Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder characterized by the development of multiple tumors involving the central nervous system (CNS). […] NF2 is caused by mutations in the NF2 gene located in the long arm of chromosome number 22 (22q12.2). The NF2 gene encodes for the protein known as merlin, which acts as a tumor suppressor gene. […] Bilateral vestibular schwannomas are the hallmark feature of NF2 and are present in approximately 90% to 95% of patients. Meningiomas are seen in approximately 50% of patients with NF2.

• #10 Neurofibromatosis type 2

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4748851/

  Neurofibromatosis type 2 is an autosomal-dominant multiple neoplasia syndrome that results from mutations in the NF2 tumour suppressor gene located on chromosome 22q. […] The NF2 tumour suppressor gene was identified in 1993. It has 17 exons that encode for a 69 kDa protein product called merlin (moesin-ezrin-radixin-like protein) or schwannomin. […] Consistent with Knudsons two-hit hypothesis of tumorigenesis, tumour formation initiates when both alleles of this gene are inactivated. […] Somatic inactivation of both alleles of this gene happens in sporadic schwannomas (90%), meningiomas (50%), and ependymomas (5%). […] Abnormal or absent merlin function (as in neurofibromatosis type 2) can disrupt tumour suppression via various mechanisms, but the importance of merlins many protein interactions in this process has not been fully elucidated.

• #11 Neurofibromatosis type 2

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4748851/

  Neurofibromatosis type 2 is an autosomal-dominant multiple neoplasia syndrome that results from mutations in the NF2 tumour suppressor gene located on chromosome 22q. […] The NF2 tumour suppressor gene was identified in 1993. It has 17 exons that encode for a 69 kDa protein product called merlin (moesin-ezrin-radixin-like protein) or schwannomin. […] Consistent with Knudsons two-hit hypothesis of tumorigenesis, tumour formation initiates when both alleles of this gene are inactivated. […] Somatic inactivation of both alleles of this gene happens in sporadic schwannomas (90%), meningiomas (50%), and ependymomas (5%). […] Abnormal or absent merlin function (as in neurofibromatosis type 2) can disrupt tumour suppression via various mechanisms, but the importance of merlins many protein interactions in this process has not been fully elucidated.

• #12 Neurofibromatosis type-2; a pathological mechanism

  https://www.wisdomlib.org/science/journal/world-journal-of-pharmaceutical-research/d/doc1382877.html

  Neurofibromatosis type 2 (NF-2) is an autosomal dominant multiple neoplasia syndrome characterized primarily by mutations in the NF-2 tumor suppressor gene located on chromosome 22q12. […] The pathogenesis of NF-2 revolves around the mutation of the NF-2 gene that encodes the merlin protein. Identified as a tumor suppressor in 1993, the NF-2 gene undergoes alterations that hinder merlins function, leading to tumorigenesis. […] The two-hit hypothesis of tumorigenesis suggests that both alleles of the NF-2 gene need to be inactivated to initiate tumor formation. Consequently, the mutations can arise either through de novo changes or inherited germline alleles, significantly impacting the internal mechanisms that regulate cellular signaling pathways, thereby allowing for the proliferation of various tumors in affected individuals. […] Merlin is a tumor suppressor protein that regulates cell growth and prevents tumor formation. Mutations in the NF2 gene disrupt Merlin’s function, leading to unregulated tumor growth.

• #13

  https://link.springer.com/article/10.1007/s40487-024-00279-2

  Neurofibromatosis type 2 (NF2)-related schwannomatosis is a rare autosomal dominant monogenic disorder caused by mutations in the NF2 gene. […] The genetic pathogenic mechanisms of the mutated NF2 gene are the basis for designing optimal gene therapy strategies with high efficiency and low toxicity. […] NF2-related schwannomatosis is caused by mutations in the NF2 gene located on chromosome 22q12.2 with a total length of approximately 95 kilobases (kb). […] Mutations in the NF2 gene produce a nonfunctional merlin protein, which leads to uncontrolled cell proliferation and tumorigenesis. […] Tumor formation in patients with NF2-related schwannomatosis is thought to be consistent with Knudson’s two-hit hypothesis of tumorigenesis. […] The identification of specific genotype and phenotype correlations has provided insights into the clinical heterogeneity observed between different families.

• #14 Neurofibromatosis type 2 (NF2): A clinical and molecular review | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-4-16

  The majority of these mutations were truncating mutations, leading to a smaller and probably non-functional protein product. […] A considerable proportion of NF2 patients, particularly milder cases, have mosaic disease, in which only a proportion of cells contain the mutated NF2 gene. […] Recent evidence suggests that up to 20-30% of NF2 cases without a family history of the disease are mosaic, carrying the mutation in too small a proportion or none of their lymphocytes to be detected from a blood sample. […] Although it is thought that effectively all schwannomas require inactivation of the NF2 gene, no reports apart from those studying NF2 protein have confirmed a 100% knock out of both copies of the NF2 gene. […] The mechanism of LOH is also not straightforward, whilst most cases involve loss of chromosome 22 or at least the long arm, a proportion are now known to be due to mitotic recombination with essentially two identical copies of a mutated NF2 gene and distal 22q. […] It is now known that between 20-40% of sporadic schwannomas are inactivated by NF2 methylation and in a similar fashion to TP16 this could involve both copies of NF2 and explain why some tumours do not harbour identifiable point mutations or LOH.

• #15 Neurofibromatosis type 2 (NF2): A clinical and molecular review | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-4-16

  Neurofibromatosis type 2 (NF2) is a dominantly inherited tumour predisposition syndrome caused by mutations in the NF2 gene on chromosome 22. […] NF2 is a genetically homogeneous condition, with no evidence for another genetic cause of classical NF2 (bilateral VS). […] Seizinger et al. were the first to show loss of constitutional heterozygosity of chromosome 22, with DNA markers lost in tumours from a patient with NF2. […] The NF2 gene was then isolated by the simultaneous discovery of constitutional and tumour deletions in a gene coding for a cell membrane-related protein, which has been termed merlin or schwannomin by the two groups who isolated it. […] Standard mutation techniques, such as Single Strand Conformational Polymorphism (SSCP) analysis or Denaturing Gradient Gel Electrophoresis, detected between 35% and 66% of pathogenic mutations.

• #16 Current Understanding of Neurofibromatosis Type 1, 2, and Schwannomatosis

  https://www.mdpi.com/1422-0067/22/11/5850

  NF2 is caused by a defect in the gene that normally produces merlin, located at 22q12.2 of chromosome 22, which regulates multiple proliferative signaling pathways. At the membrane, merlin blocks signaling caused by integrins and tyrosine receptor kinases. Merlin can also inhibit downstream signalings, including the p21-activated kinase signaling, Ras/Raf/MEK/ERK, FAK/Src, PI3K/AKT, Rac/PAK/JNK, mTORC1, and Wnt/β-catenin pathways. […] The growth of schwannomas requires inactivation of both NF2 alleles. The “second hit” occurs through loss of the entire NF2 gene and most of chromosome 22. Various types of mutations, such as protein-truncating alterations (frameshift deletions/insertions and nonsense mutations), splice-site mutations, missense mutations, are identified. Truncating mutations (nonsense and frameshifts) are the most frequent germline event and cause the most severe disease. […] The NF2 gene product involves multiple molecular pathways in cell growth. Some studies reported on the efficacy of everolimus, an oral inhibitor of the mTORC1, for progressive vestibular schwannomas in NF2 patients.

• #17 Neurofibromatosis Type 2: Case Presentation and Review of the Literature | IntechOpen

  https://www.intechopen.com/chapters/1136889

  Nonsense/frameshift mutations produce a truncated protein and tend to be associated with a more severe phenotype, earlier onset, more rapid disease progression, and higher tumor burden with more spinal and intracranial tumors in addition to vestibular schwannomas. […] Although many patients have symptoms before coming to medical attention, the average age of diagnosis of NF2 is 25 years. […] Vestibular schwannomas are the most common tumor in NF2 and are usually present bilaterally. […] Bilateral vestibular schwannomas are the distinctive feature of neurofibromatosis type 2 and are identified in 90-95% of patients. […] Meningiomas are the second most common tumor type in NF2, and the most common central nervous system tumor occurring throughout the central nervous system in 50-75% of individuals, often with multiple tumors.

• #18 NF2-related schwannomatosis | MedLink Neurology

  https://www.medlink.com/articles/nf2-related-schwannomatosis

  Merlin inhibits downstream pathways, such as the Wnt/-catenin, p21, Ras/Raf/MEK/ERK, Rac/PAK/JNK, PI3K/AKT, FAK/Src, and mTORC1 pathways. Merlin does not stay at the cell membrane but also migrates to the nucleus and induces growth suppression through inhibition of CRL4DCAF1, the E3 ubiquitin ligase, which regulates integrin and tyrosine receptor kinase expression. […] A de novo mutation results in somatic mosaicism, which may hinder a molecular diagnosis unless the specific tumor tissue is examined. Schwannoma growth requires the inactivation of both the two neurofibromatosis 2 alleles. This mutation may be a nonsense, a splice-site, or a missense mutation, or it may be a frameshift deletion or insertion. Nonsense and frameshift mutations resulting in protein-truncating changes are the most commonly identified germline events and result in the most severe phenotype with a younger age at diagnosis and a higher tumor burden. On the other hand, missense and in-frame deletions are linked to milder disease courses. Similarly, mutations in exons 14 and 15 in the latter parts of the NF2 gene are associated with a milder disease and smaller incidence of meningiomas.

• #19 Neurofibromatosis Type 2 | Ento Key

  https://entokey.com/neurofibromatosis-type-2/

  Neurofibromatosis type 2 (NF2) results from the inheritance of a mutation in merlin (or schwannomin) protein on chromosome 22. […] The recent identification of the gene responsible for NF2 has significantly advanced our understanding of the molecular pathology, as well as the factors responsible for the clinical heterogeneity among patients with NF2. […] The loss of function of the merlin protein therefore could result in a loss of contact inhibition and consequently lead to tumorigenesis. […] NF2 gene defects have been detected in other malignant disorders including meningiomas, malignant mesotheliomas, melanomas, and breast carcinomas. […] Approximately 50% of affected patients have no family history of NF2. […] Genotype-phenotype correlation studies suggest that mutations in the NF2 gene, which result in protein truncation, are associated with a more severe clinical presentation of NF2 (Wishart type), whereas missense and splice site mutations are associated with a milder (Gardner type) form of the disease. […] Although mutations in the NF2 gene play a dominant role in the biology of VS, it is also possible that other genetic loci contribute to the development of VS.

• #20 NF2-related schwannomatosis | MedLink Neurology

  https://www.medlink.com/articles/nf2-related-schwannomatosis

  Merlin inhibits downstream pathways, such as the Wnt/-catenin, p21, Ras/Raf/MEK/ERK, Rac/PAK/JNK, PI3K/AKT, FAK/Src, and mTORC1 pathways. Merlin does not stay at the cell membrane but also migrates to the nucleus and induces growth suppression through inhibition of CRL4DCAF1, the E3 ubiquitin ligase, which regulates integrin and tyrosine receptor kinase expression. […] A de novo mutation results in somatic mosaicism, which may hinder a molecular diagnosis unless the specific tumor tissue is examined. Schwannoma growth requires the inactivation of both the two neurofibromatosis 2 alleles. This mutation may be a nonsense, a splice-site, or a missense mutation, or it may be a frameshift deletion or insertion. Nonsense and frameshift mutations resulting in protein-truncating changes are the most commonly identified germline events and result in the most severe phenotype with a younger age at diagnosis and a higher tumor burden. On the other hand, missense and in-frame deletions are linked to milder disease courses. Similarly, mutations in exons 14 and 15 in the latter parts of the NF2 gene are associated with a milder disease and smaller incidence of meningiomas.

• #21 Neurofibromatosis type-2; a pathological mechanism

  https://www.wisdomlib.org/science/journal/world-journal-of-pharmaceutical-research/d/doc1382877.html

  Neurofibromatosis type 2 (NF-2) is an autosomal dominant multiple neoplasia syndrome characterized primarily by mutations in the NF-2 tumor suppressor gene located on chromosome 22q12. […] The pathogenesis of NF-2 revolves around the mutation of the NF-2 gene that encodes the merlin protein. Identified as a tumor suppressor in 1993, the NF-2 gene undergoes alterations that hinder merlins function, leading to tumorigenesis. […] The two-hit hypothesis of tumorigenesis suggests that both alleles of the NF-2 gene need to be inactivated to initiate tumor formation. Consequently, the mutations can arise either through de novo changes or inherited germline alleles, significantly impacting the internal mechanisms that regulate cellular signaling pathways, thereby allowing for the proliferation of various tumors in affected individuals. […] Merlin is a tumor suppressor protein that regulates cell growth and prevents tumor formation. Mutations in the NF2 gene disrupt Merlin’s function, leading to unregulated tumor growth.

• #22 Neurofibromatosis type 2 (NF2): A clinical and molecular review | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-4-16

  The majority of these mutations were truncating mutations, leading to a smaller and probably non-functional protein product. […] A considerable proportion of NF2 patients, particularly milder cases, have mosaic disease, in which only a proportion of cells contain the mutated NF2 gene. […] Recent evidence suggests that up to 20-30% of NF2 cases without a family history of the disease are mosaic, carrying the mutation in too small a proportion or none of their lymphocytes to be detected from a blood sample. […] Although it is thought that effectively all schwannomas require inactivation of the NF2 gene, no reports apart from those studying NF2 protein have confirmed a 100% knock out of both copies of the NF2 gene. […] The mechanism of LOH is also not straightforward, whilst most cases involve loss of chromosome 22 or at least the long arm, a proportion are now known to be due to mitotic recombination with essentially two identical copies of a mutated NF2 gene and distal 22q. […] It is now known that between 20-40% of sporadic schwannomas are inactivated by NF2 methylation and in a similar fashion to TP16 this could involve both copies of NF2 and explain why some tumours do not harbour identifiable point mutations or LOH.

• #23 Neurofibromatosis type 2 (NF2): A clinical and molecular review | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-4-16

  The majority of these mutations were truncating mutations, leading to a smaller and probably non-functional protein product. […] A considerable proportion of NF2 patients, particularly milder cases, have mosaic disease, in which only a proportion of cells contain the mutated NF2 gene. […] Recent evidence suggests that up to 20-30% of NF2 cases without a family history of the disease are mosaic, carrying the mutation in too small a proportion or none of their lymphocytes to be detected from a blood sample. […] Although it is thought that effectively all schwannomas require inactivation of the NF2 gene, no reports apart from those studying NF2 protein have confirmed a 100% knock out of both copies of the NF2 gene. […] The mechanism of LOH is also not straightforward, whilst most cases involve loss of chromosome 22 or at least the long arm, a proportion are now known to be due to mitotic recombination with essentially two identical copies of a mutated NF2 gene and distal 22q. […] It is now known that between 20-40% of sporadic schwannomas are inactivated by NF2 methylation and in a similar fashion to TP16 this could involve both copies of NF2 and explain why some tumours do not harbour identifiable point mutations or LOH.

• #24 The genetic landscape and possible therapeutics of neurofibromatosis type 2 | Cancer Cell International | Full Text

  https://cancerci.biomedcentral.com/articles/10.1186/s12935-023-02940-8

  The types of pathogenic mutations can predict the number of intracranial meningiomas, spinal tumors, and tumors of peripheral nerves. […] The involved site also matters. Mutations in the amino-terminal domain of NF2 proteins are associated with early tumor onset with more severe disease progression. […] The function of ERM proteins is regulated by transitioning between the open and closed states, leading to activation and deactivation of the protein, respectively. […] Merlin regulates cell survival and proliferation in response to multiple proliferative signaling pathways. […] The mechanisms underlying how merlin regulates cell proliferation are yet to be elucidated. […] The inactivation of merlin can lead to uncontrolled cell proliferation and tumorigenesis, especially in the nervous system. […] A comprehensive understanding of molecular mechanisms in tumor progression of NF2-related tumors will provide opportunities for exploring more efficient treatments.

• #25 Current progress in genomics and targeted therapies for neurofibromatosis type 2

  https://www.jstage.jst.go.jp/article/fms/advpub/0/advpub_2023-05/_html/-char/ja

  Merlin exerts inhibitory effects on multiple receptor tyrosine kinases (RTK) such as the ErbB receptor, platelet-derived growth factor receptor (PDGFR), insulin-like growth factor 1 receptor (IGF1R), and vascular endothelial growth factor receptor (VEGFR). […] Merlin switches from an active closed state to an inactive open state by phosphorylation at serine-518 on the carboxy-terminal domain. […] The type of NF2 mutation is responsible for the number of lesions of the intracranial meningiomas, spinal cord, and peripheral nerves. […] The phenotypes are also different between germline mutation and somatic mosaicism. […] Understanding the pathogenesis and employing genetic analysis can help diagnose NF2 early, especially the de novo types.

• #26 The genetic landscape and possible therapeutics of neurofibromatosis type 2 | Cancer Cell International | Full Text

  https://cancerci.biomedcentral.com/articles/10.1186/s12935-023-02940-8

  The types of pathogenic mutations can predict the number of intracranial meningiomas, spinal tumors, and tumors of peripheral nerves. […] The involved site also matters. Mutations in the amino-terminal domain of NF2 proteins are associated with early tumor onset with more severe disease progression. […] The function of ERM proteins is regulated by transitioning between the open and closed states, leading to activation and deactivation of the protein, respectively. […] Merlin regulates cell survival and proliferation in response to multiple proliferative signaling pathways. […] The mechanisms underlying how merlin regulates cell proliferation are yet to be elucidated. […] The inactivation of merlin can lead to uncontrolled cell proliferation and tumorigenesis, especially in the nervous system. […] A comprehensive understanding of molecular mechanisms in tumor progression of NF2-related tumors will provide opportunities for exploring more efficient treatments.

• #27 NF2-related schwannomatosis | MedLink Neurology

  https://www.medlink.com/articles/nf2-related-schwannomatosis

  Merlin inhibits downstream pathways, such as the Wnt/-catenin, p21, Ras/Raf/MEK/ERK, Rac/PAK/JNK, PI3K/AKT, FAK/Src, and mTORC1 pathways. Merlin does not stay at the cell membrane but also migrates to the nucleus and induces growth suppression through inhibition of CRL4DCAF1, the E3 ubiquitin ligase, which regulates integrin and tyrosine receptor kinase expression. […] A de novo mutation results in somatic mosaicism, which may hinder a molecular diagnosis unless the specific tumor tissue is examined. Schwannoma growth requires the inactivation of both the two neurofibromatosis 2 alleles. This mutation may be a nonsense, a splice-site, or a missense mutation, or it may be a frameshift deletion or insertion. Nonsense and frameshift mutations resulting in protein-truncating changes are the most commonly identified germline events and result in the most severe phenotype with a younger age at diagnosis and a higher tumor burden. On the other hand, missense and in-frame deletions are linked to milder disease courses. Similarly, mutations in exons 14 and 15 in the latter parts of the NF2 gene are associated with a milder disease and smaller incidence of meningiomas.

• #28 Neurofibromatosis type 2

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4748851/

  Neurofibromatosis type 2 is an autosomal-dominant multiple neoplasia syndrome that results from mutations in the NF2 tumour suppressor gene located on chromosome 22q. […] The NF2 tumour suppressor gene was identified in 1993. It has 17 exons that encode for a 69 kDa protein product called merlin (moesin-ezrin-radixin-like protein) or schwannomin. […] Consistent with Knudsons two-hit hypothesis of tumorigenesis, tumour formation initiates when both alleles of this gene are inactivated. […] Somatic inactivation of both alleles of this gene happens in sporadic schwannomas (90%), meningiomas (50%), and ependymomas (5%). […] Abnormal or absent merlin function (as in neurofibromatosis type 2) can disrupt tumour suppression via various mechanisms, but the importance of merlins many protein interactions in this process has not been fully elucidated.

• #29 NF2: An underestimated player in cancer metabolic reprogramming and tumor immunity | npj Precision Oncology

  https://www.nature.com/articles/s41698-024-00627-5

  Neurofibromatosis type 2 (NF2) is a tumor suppressor gene implicated in various tumors, including mesothelioma, schwannomas, and meningioma. As a member of the ezrin, radixin, and moesin (ERM) family of proteins, merlin, which is encoded by NF2, regulates diverse cellular events and signalling pathways, such as the Hippo, mTOR, RAS, and cGAS-STING pathways. However, the biological role of NF2 in tumorigenesis has not been fully elucidated. […] In addition to the functional inactivation of NF2, the codeficiency of other genes, such as cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B), BRCA1-associated protein-1 (BAP1), and large tumor suppressor 2 (LATS2), results in unique tumor characteristics that should be considered in clinical treatment decisions. […] We also explored the current understanding of how NF2 deficiency drives tumorigenesis from the perspective of cancer metabolism reprogramming and antitumour immunity.

• #30 Neurofibromatosis type 2

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4748851/

  Merlin is a unique tumour suppressor protein because it localises to the cell membranecytoskeletal interface. […] These oncogenic pathways are crucial for promotion of cell growth, protein translation, and cellular proliferation. […] Drugs targeting these pathways (ie, sorafenib, trastuzumab, lapatinib, LY294002, protein kinase inhibitors, and p21-activated kinase inhibitors) and tumour angiogenesis (bevacizumab) are under preclinical or early clinical investigation and are potential treatments for neurofibromatosis type 2.

• #31 The genetic landscape and possible therapeutics of neurofibromatosis type 2 | Cancer Cell International | Full Text

  https://cancerci.biomedcentral.com/articles/10.1186/s12935-023-02940-8

  The types of pathogenic mutations can predict the number of intracranial meningiomas, spinal tumors, and tumors of peripheral nerves. […] The involved site also matters. Mutations in the amino-terminal domain of NF2 proteins are associated with early tumor onset with more severe disease progression. […] The function of ERM proteins is regulated by transitioning between the open and closed states, leading to activation and deactivation of the protein, respectively. […] Merlin regulates cell survival and proliferation in response to multiple proliferative signaling pathways. […] The mechanisms underlying how merlin regulates cell proliferation are yet to be elucidated. […] The inactivation of merlin can lead to uncontrolled cell proliferation and tumorigenesis, especially in the nervous system. […] A comprehensive understanding of molecular mechanisms in tumor progression of NF2-related tumors will provide opportunities for exploring more efficient treatments.

• #32 Neurofibromatosis Type 2 Protein, NF2: An Uncoventional Cell Cycle Regulator | Anticancer Research

  https://ar.iiarjournals.org/content/33/1/1

  While NF2 has not been shown to elicit a direct effect on the cell cycle, several studies have demonstrated its influence on cell cycle progression. For example, re-introduction of NF2 induces cell cycle arrest in numerous cells types including, rat and human schwannomas, primary endothelial cells, mesotheliomas, and patient-derived meningiomas. These studies have led to the speculation that NF2 may indeed regulate progression of the cell cycle across a range of cell types. […] The nuclear translocation of NF2 appears to be mediated by both its phosphorylation status and the phase of the cell cycle. NF2 is thought to exist in two conformations, known as the open and closed conformations, which are based on the phosphorylation status of serine residue number 518 (Ser518). Phosphorylation of Ser518, by either p21-activated kinases (PAKs), Rac GTPase, or protein kinase A (PKA), allows NF2 to adopt an open conformation which is considered to be inactive, as the open conformation is unable to inhibit growth in vitro. However, tumor suppressive functions have ascribed to the phosphorylated form of this protein.

• #33 The genetic landscape and possible therapeutics of neurofibromatosis type 2 | Cancer Cell International | Full Text

  https://cancerci.biomedcentral.com/articles/10.1186/s12935-023-02940-8

  The types of pathogenic mutations can predict the number of intracranial meningiomas, spinal tumors, and tumors of peripheral nerves. […] The involved site also matters. Mutations in the amino-terminal domain of NF2 proteins are associated with early tumor onset with more severe disease progression. […] The function of ERM proteins is regulated by transitioning between the open and closed states, leading to activation and deactivation of the protein, respectively. […] Merlin regulates cell survival and proliferation in response to multiple proliferative signaling pathways. […] The mechanisms underlying how merlin regulates cell proliferation are yet to be elucidated. […] The inactivation of merlin can lead to uncontrolled cell proliferation and tumorigenesis, especially in the nervous system. […] A comprehensive understanding of molecular mechanisms in tumor progression of NF2-related tumors will provide opportunities for exploring more efficient treatments.

• #34 The genetic landscape and possible therapeutics of neurofibromatosis type 2 | Cancer Cell International | Full Text

  https://cancerci.biomedcentral.com/articles/10.1186/s12935-023-02940-8

  The types of pathogenic mutations can predict the number of intracranial meningiomas, spinal tumors, and tumors of peripheral nerves. […] The involved site also matters. Mutations in the amino-terminal domain of NF2 proteins are associated with early tumor onset with more severe disease progression. […] The function of ERM proteins is regulated by transitioning between the open and closed states, leading to activation and deactivation of the protein, respectively. […] Merlin regulates cell survival and proliferation in response to multiple proliferative signaling pathways. […] The mechanisms underlying how merlin regulates cell proliferation are yet to be elucidated. […] The inactivation of merlin can lead to uncontrolled cell proliferation and tumorigenesis, especially in the nervous system. […] A comprehensive understanding of molecular mechanisms in tumor progression of NF2-related tumors will provide opportunities for exploring more efficient treatments.

• #35 Neurofibromatosis type 2 | Radiology Reference Article | Radiopaedia.org

  https://radiopaedia.org/articles/neurofibromatosis-type-2-3?embed_domain=external.radpair.com%27%5B0%5Dfavicon.icoradiopaedia-icon-144.pngfavicon.icofavicon.ico&lang=us

  Neurofibromatosis type 2 (NF2) is a rare autosomal dominant neurocutaneous disorder (phakomatosis) manifesting as a development of multiple CNS tumors. […] The NF2 gene is located on the long arm of chromosome 22 (22q12) and encodes the merlin protein (also known as „schwannomin”). It plays a role in contact inhibition of growth and has tumor suppressor function at least in part according to this mechanism. […] Mutations in NF2 cause loss of protein function, resulting in a predisposition to tumor formation throughout the nervous system.

• #36 Neurofibromatosis type II – wikidoc

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

  NF II is caused by a defect in the gene that normally gives rise to a product called Merlin or Schwannomin, located on chromosome 22 band q11-13.1. This peptide is thought to have a tumor-suppressive function. […] It is known that Merlin’s deficiency can result in unmediated progression through the cell cycle due to the lack of contact-mediated tumour suppression, sufficient to result in the tumors characteristic of Neurofibromatosis type II. […] The NF II gene is presumed to result in either a failure to synthesize Merlin or the production of a defective peptide that lacks the normal tumor-suppressive effect. […] Mutations in the Schwannomin-gene are thought to alter the movement and shape of affected cells with loss of contact inhibition.

• #37 Current Understanding of Neurofibromatosis Type 1, 2, and Schwannomatosis

  https://www.mdpi.com/1422-0067/22/11/5850

  NF2 is caused by a defect in the gene that normally produces merlin, located at 22q12.2 of chromosome 22, which regulates multiple proliferative signaling pathways. At the membrane, merlin blocks signaling caused by integrins and tyrosine receptor kinases. Merlin can also inhibit downstream signalings, including the p21-activated kinase signaling, Ras/Raf/MEK/ERK, FAK/Src, PI3K/AKT, Rac/PAK/JNK, mTORC1, and Wnt/β-catenin pathways. […] The growth of schwannomas requires inactivation of both NF2 alleles. The “second hit” occurs through loss of the entire NF2 gene and most of chromosome 22. Various types of mutations, such as protein-truncating alterations (frameshift deletions/insertions and nonsense mutations), splice-site mutations, missense mutations, are identified. Truncating mutations (nonsense and frameshifts) are the most frequent germline event and cause the most severe disease. […] The NF2 gene product involves multiple molecular pathways in cell growth. Some studies reported on the efficacy of everolimus, an oral inhibitor of the mTORC1, for progressive vestibular schwannomas in NF2 patients.

• #38 Neurofibromatosis type II – Wikipedia

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

  Neurofibromatosis type II (NF2) is caused by mutations of the „Merlin” gene, which seems to influence the form and movement of cells. […] NF2 is caused by a defect in the gene that normally gives rise to a product called Merlin or Schwannomin, located on chromosome 22 band q11-13.1. Merlin was first discovered as a structural protein functioning as an actin cytoskeleton regulator. Later merlin’s tumour suppressant role was described. Merlin regulates multiple proliferative signalling cascades such as receptor tyrosine kinase signalling, p21-activated kinase signalling, Ras signalling, MEK-ERK cascade, MST-YAP cascade. […] It has been shown that Merlin inhibits Rac1 which is crucial for cell motility and tumour invasion. […] It is known that Merlin’s deficiency can result in unmediated progression through the cell cycle due to the lack of contact-mediated tumour suppression, mainly because of the cell:cell junction disruption, sufficient to result in the tumors characteristic of Neurofibromatosis type II.

• #39 Neurofibromatosis Type 2 (NF2) and the Implications for Vestibular Schwannoma and Meningioma Pathogenesis

  https://www.mdpi.com/1422-0067/22/2/690

  Patients diagnosed with neurofibromatosis type 2 (NF2) are extremely likely to develop meningiomas, in addition to vestibular schwannomas. […] In NF2, patients have mutations in the NF2 gene, specifically with loss of function in a tumor-suppressor protein that has a number of synonymous names, including: Merlin, Neurofibromin 2, and schwannomin. […] The Hippo Tumor Suppressor pathway is regulated upstream by Merlin. This pathway is critical in regulating cell proliferation and apoptosis, characteristics that are important for tumor progression. […] Mutations of the NF2 gene are strongly associated with NF2 diagnosis, leading to benign proliferative conditions such as vestibular schwannomas and meningiomas. […] Loss of chromosome 22 has been widely implicated in the pathogenesis of meningioma, sharing a common pathway for tumorigenesis with NF2 patients due to the presence of neurofibromin on chromosome 22q12.2.

• #40 NF2: An underestimated player in cancer metabolic reprogramming and tumor immunity | npj Precision Oncology

  https://www.nature.com/articles/s41698-024-00627-5

  The Hippo pathway is implicated in many aspects of tumors, including organ development, tissue regeneration, and epithelial-to-mesenchymal transition (EMT). Merlin negatively regulates the Hippo pathway in the cytoplasm and the nucleus. […] In neurofibromatosis and meningioma, evidence shows that loss of merlin promotes activation of the PI3K-AKT-mTOR pathway, leading to Schwann cell proliferation. […] Several lines of evidence suggest a close relationship between merlin and the rat sarcoma-causing gene (RAS), among which merlin can inhibit the RAS-mediated signalling pathway. […] The first exploration of the relationship between NF2 and Ras could date back to 1994, when Tikoo et al. reported that the overexpression of full-length NF2 could reverse the Ras-induced malignant phenotype. […] Overall, cooccurring deficiencies in BAP1, NF2, and CDKN2A/B might play an instructive role in tumor immunity and are closely related to patient prognosis.

• #41 NF2: An underestimated player in cancer metabolic reprogramming and tumor immunity | npj Precision Oncology

  https://www.nature.com/articles/s41698-024-00627-5

  The Hippo pathway is implicated in many aspects of tumors, including organ development, tissue regeneration, and epithelial-to-mesenchymal transition (EMT). Merlin negatively regulates the Hippo pathway in the cytoplasm and the nucleus. […] In neurofibromatosis and meningioma, evidence shows that loss of merlin promotes activation of the PI3K-AKT-mTOR pathway, leading to Schwann cell proliferation. […] Several lines of evidence suggest a close relationship between merlin and the rat sarcoma-causing gene (RAS), among which merlin can inhibit the RAS-mediated signalling pathway. […] The first exploration of the relationship between NF2 and Ras could date back to 1994, when Tikoo et al. reported that the overexpression of full-length NF2 could reverse the Ras-induced malignant phenotype. […] Overall, cooccurring deficiencies in BAP1, NF2, and CDKN2A/B might play an instructive role in tumor immunity and are closely related to patient prognosis.

• #42 Neurofibromatosis Type 2: Current Trends and Future Directions for Targeted Biologic Therapies | IntechOpen

  https://www.intechopen.com/chapters/70156

  Merlin is also involved in regulating a number of pathways and intracellular targets relevant to cellular proliferation and survival. […] In NF2 preclinical studies, loss of merlin activity leads to Schwann cell growth via activation of the PI3K/Akt pathway. […] In addition, gene-expression profiling of sporadic and NF2-associated VS demonstrated overexpression of the PI3K/Akt/mTOR pathway. […] Merlin is considered a negative regulator of mTOR. […] Loss of Merlin function leads to constitutive mTOR signaling in NF2-deficient tumors, including schwannomas, meningiomas, and mesotheliomas. […] In preclinical studies, inhibition with mTORC1 reversed the phenotypic consequences of NF2-deficient schwannoma and meningioma cell lines.

• #43 NF2: An underestimated player in cancer metabolic reprogramming and tumor immunity | npj Precision Oncology

  https://www.nature.com/articles/s41698-024-00627-5

  The Hippo pathway is implicated in many aspects of tumors, including organ development, tissue regeneration, and epithelial-to-mesenchymal transition (EMT). Merlin negatively regulates the Hippo pathway in the cytoplasm and the nucleus. […] In neurofibromatosis and meningioma, evidence shows that loss of merlin promotes activation of the PI3K-AKT-mTOR pathway, leading to Schwann cell proliferation. […] Several lines of evidence suggest a close relationship between merlin and the rat sarcoma-causing gene (RAS), among which merlin can inhibit the RAS-mediated signalling pathway. […] The first exploration of the relationship between NF2 and Ras could date back to 1994, when Tikoo et al. reported that the overexpression of full-length NF2 could reverse the Ras-induced malignant phenotype. […] Overall, cooccurring deficiencies in BAP1, NF2, and CDKN2A/B might play an instructive role in tumor immunity and are closely related to patient prognosis.

• #44 Current Understanding of Neurofibromatosis Type 1, 2, and Schwannomatosis

  https://www.mdpi.com/1422-0067/22/11/5850

  NF2 is caused by a defect in the gene that normally produces merlin, located at 22q12.2 of chromosome 22, which regulates multiple proliferative signaling pathways. At the membrane, merlin blocks signaling caused by integrins and tyrosine receptor kinases. Merlin can also inhibit downstream signalings, including the p21-activated kinase signaling, Ras/Raf/MEK/ERK, FAK/Src, PI3K/AKT, Rac/PAK/JNK, mTORC1, and Wnt/β-catenin pathways. […] The growth of schwannomas requires inactivation of both NF2 alleles. The “second hit” occurs through loss of the entire NF2 gene and most of chromosome 22. Various types of mutations, such as protein-truncating alterations (frameshift deletions/insertions and nonsense mutations), splice-site mutations, missense mutations, are identified. Truncating mutations (nonsense and frameshifts) are the most frequent germline event and cause the most severe disease. […] The NF2 gene product involves multiple molecular pathways in cell growth. Some studies reported on the efficacy of everolimus, an oral inhibitor of the mTORC1, for progressive vestibular schwannomas in NF2 patients.

• #45 Neurofibromatosis Type 2: Current Trends and Future Directions for Targeted Biologic Therapies | IntechOpen

  https://www.intechopen.com/chapters/70156

  Merlin is a multifunctional protein that is involved with the regulation of intra- and extracellular molecules and biologic pathways that are important for cellular structure, survival, proliferation, and contact-dependent inhibition. […] Increased research efforts have enabled the discovery of various molecular pathways and targets relevant to the pathogenesis of NF2-related tumors. […] NF2-VS have increased expression of VEGF, a powerful mediator of tumor angiogenesis. […] Additionally, VS are highly vascular tumors, making anti-angiogenesis an appealing option that has been evaluated in NF2 patients in clinical studies. […] Another growth factor relevant to NF2-pathogenesis is PDGFR. […] The ErbB family of receptor tyrosine kinases has also been increasingly studied in NF2, primarily ErbB1 (EGFR).

• #46 Current progress in genomics and targeted therapies for neurofibromatosis type 2

  https://www.jstage.jst.go.jp/article/fms/advpub/0/advpub_2023-05/_html/-char/ja

  Merlin exerts inhibitory effects on multiple receptor tyrosine kinases (RTK) such as the ErbB receptor, platelet-derived growth factor receptor (PDGFR), insulin-like growth factor 1 receptor (IGF1R), and vascular endothelial growth factor receptor (VEGFR). […] Merlin switches from an active closed state to an inactive open state by phosphorylation at serine-518 on the carboxy-terminal domain. […] The type of NF2 mutation is responsible for the number of lesions of the intracranial meningiomas, spinal cord, and peripheral nerves. […] The phenotypes are also different between germline mutation and somatic mosaicism. […] Understanding the pathogenesis and employing genetic analysis can help diagnose NF2 early, especially the de novo types.

• #47 The genetic landscape and possible therapeutics of neurofibromatosis type 2 | springermedizin.de

  https://www.springermedizin.de/the-genetic-landscape-and-possible-therapeutics-of-neurofibromat/25394884

  Neurofibromatosis type 2 (NF2) is caused by loss-of-function mutations in the NF2 gene on chromosome 22, leading the merlin protein to malfunction. […] Recent advances in genetics and molecular biology have allowed identifying and targeting of underlying pathways in the pathogenesis of NF2. […] NF2 is caused by loss of function mutations, deletions, or epigenetic modifications of the NF2 gene (OMIM: 607379). […] Tumorigenesis occurs upon merlin loss of function by modifying downstream signaling pathways. […] The NF2 gene encodes a 70-kDa protein called merlin, mainly acting as a tumor suppressor and participating in diverse cell signaling pathways. […] The interaction of merlin with the aforementioned biomarkers has another face. It has been demonstrated that merlin (as a tumor suppressor) has inhibitory effects on PI3K, Raf/ERK, Wnt/-catenin, RTKs, and mTOR.

• #48 NF2-related schwannomatosis | MedLink Neurology

  https://www.medlink.com/articles/nf2-related-schwannomatosis

  Merlin inhibits downstream pathways, such as the Wnt/-catenin, p21, Ras/Raf/MEK/ERK, Rac/PAK/JNK, PI3K/AKT, FAK/Src, and mTORC1 pathways. Merlin does not stay at the cell membrane but also migrates to the nucleus and induces growth suppression through inhibition of CRL4DCAF1, the E3 ubiquitin ligase, which regulates integrin and tyrosine receptor kinase expression. […] A de novo mutation results in somatic mosaicism, which may hinder a molecular diagnosis unless the specific tumor tissue is examined. Schwannoma growth requires the inactivation of both the two neurofibromatosis 2 alleles. This mutation may be a nonsense, a splice-site, or a missense mutation, or it may be a frameshift deletion or insertion. Nonsense and frameshift mutations resulting in protein-truncating changes are the most commonly identified germline events and result in the most severe phenotype with a younger age at diagnosis and a higher tumor burden. On the other hand, missense and in-frame deletions are linked to milder disease courses. Similarly, mutations in exons 14 and 15 in the latter parts of the NF2 gene are associated with a milder disease and smaller incidence of meningiomas.

• #49 Cellular mechanisms of heterogeneity in NF2-mutant schwannoma | Nature Communications

  https://www.nature.com/articles/s41467-023-37226-0

  Schwannomas are common sporadic tumors and hallmarks of familial neurofibromatosis type 2 (NF2) that develop predominantly on cranial and spinal nerves. Virtually all schwannomas result from inactivation of the NF2 tumor suppressor gene with few, if any, cooperating mutations. […] How heterogeneity develops in NF2-mutant schwannomas is unknown. We have found that loss of the membrane:cytoskeleton-associated NF2 tumor suppressor, merlin, yields unstable intrinsic polarity and enables Nf2/ Schwann cells to adopt distinct programs of ErbB ligand production and polarized signaling, suggesting a self-generated model of schwannoma heterogeneity. […] Our studies highlight the importance of intrinsic mechanisms of heterogeneity across human cancers. […] We have found that NF2-deficient SCs exhibit unstable polarity and can adopt distinct phenotypic states featuring coordinated auto/paracrine ErbB ligand and polarity gene expression and polarized cytoskeletal organization, suggesting a model of self-generated heterogeneity that could explain the notoriously variable clinical and therapeutic behaviors of schwannomas.

• #50 Cellular mechanisms of heterogeneity in NF2-mutant schwannoma | Nature Communications

  https://www.nature.com/articles/s41467-023-37226-0

  Schwannomas are common sporadic tumors and hallmarks of familial neurofibromatosis type 2 (NF2) that develop predominantly on cranial and spinal nerves. Virtually all schwannomas result from inactivation of the NF2 tumor suppressor gene with few, if any, cooperating mutations. […] How heterogeneity develops in NF2-mutant schwannomas is unknown. We have found that loss of the membrane:cytoskeleton-associated NF2 tumor suppressor, merlin, yields unstable intrinsic polarity and enables Nf2/ Schwann cells to adopt distinct programs of ErbB ligand production and polarized signaling, suggesting a self-generated model of schwannoma heterogeneity. […] Our studies highlight the importance of intrinsic mechanisms of heterogeneity across human cancers. […] We have found that NF2-deficient SCs exhibit unstable polarity and can adopt distinct phenotypic states featuring coordinated auto/paracrine ErbB ligand and polarity gene expression and polarized cytoskeletal organization, suggesting a model of self-generated heterogeneity that could explain the notoriously variable clinical and therapeutic behaviors of schwannomas.

• #51 Neurofibromatosis type II – wikidoc

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

  NF II is caused by a defect in the gene that normally gives rise to a product called Merlin or Schwannomin, located on chromosome 22 band q11-13.1. This peptide is thought to have a tumor-suppressive function. […] It is known that Merlin’s deficiency can result in unmediated progression through the cell cycle due to the lack of contact-mediated tumour suppression, sufficient to result in the tumors characteristic of Neurofibromatosis type II. […] The NF II gene is presumed to result in either a failure to synthesize Merlin or the production of a defective peptide that lacks the normal tumor-suppressive effect. […] Mutations in the Schwannomin-gene are thought to alter the movement and shape of affected cells with loss of contact inhibition.

• #52 Neurofibromatosis Type 2 Protein, NF2: An Uncoventional Cell Cycle Regulator | Anticancer Research

  https://ar.iiarjournals.org/content/33/1/1

  Neurofibromatosis type 2 protein (NF2) is an underappreciated tumor suppressor involved in a broad range of nervous system tumors. Inactivation of the NF2 gene leads to neurofibromatosis type-2, which is characterized by multiple benign nervous system tumors and mutations in the gene have been demonstrated in many other tumor types as well. All tumors, regardless of location or grade, lack a fundamental control over cell cycle progression. Historically, NF2 is an unconventional tumor suppressor protein in that it does not directly influence the cell cycle. NF2 links receptors at the plasma membrane to their cytoplasmic kinases to facilitate contact inhibition. However, NF2 can also interact with an array of cytoplasmic and nuclear proteins that affect cell cycle progression. Furthermore, through some of these pathways, NF2 may reverse the functional inhibition of conventional tumor suppressor pathways. Here we review mechanisms utilized by NF2 to regain control of the cell cycle.

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

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

  Neurofibromatosis types 1 and 2 are a group of neurocutaneous syndromes resulting from disorders in cell regulation. […] Neurofibromatosis type 2 is a less common condition, seen in approximately 1 in 50,000 individuals and is characterized more often by central nervous system tumors. […] The classic feature of neurofibromatosis type 2 is bilateral vestibular schwannomas, which occur in up to 95% of patients with the disorder. […] CNS tumors, including meningiomas and gliomas, are frequent occurrences in patients with NF-2. […] NF2 also encodes a tumor-suppressor gene on chromosome 22q12.2, extending 110 kilobases. […] Normally, this gene codes for the protein merlin, a regulator of cell growth, especially in Schwann cells. […] Merlin acts as a cytoskeletal linker, interacting with multiple membrane proteins to regulate cell growth, motility, and remodelling.

• #54 Cellular mechanisms of heterogeneity in NF2-mutant schwannoma | Nature Communications

  https://www.nature.com/articles/s41467-023-37226-0

  Schwannomas are common sporadic tumors and hallmarks of familial neurofibromatosis type 2 (NF2) that develop predominantly on cranial and spinal nerves. Virtually all schwannomas result from inactivation of the NF2 tumor suppressor gene with few, if any, cooperating mutations. […] How heterogeneity develops in NF2-mutant schwannomas is unknown. We have found that loss of the membrane:cytoskeleton-associated NF2 tumor suppressor, merlin, yields unstable intrinsic polarity and enables Nf2/ Schwann cells to adopt distinct programs of ErbB ligand production and polarized signaling, suggesting a self-generated model of schwannoma heterogeneity. […] Our studies highlight the importance of intrinsic mechanisms of heterogeneity across human cancers. […] We have found that NF2-deficient SCs exhibit unstable polarity and can adopt distinct phenotypic states featuring coordinated auto/paracrine ErbB ligand and polarity gene expression and polarized cytoskeletal organization, suggesting a model of self-generated heterogeneity that could explain the notoriously variable clinical and therapeutic behaviors of schwannomas.

• #55 Cellular mechanisms of heterogeneity in NF2-mutant schwannoma | Nature Communications

  https://www.nature.com/articles/s41467-023-37226-0

  Our findings provide mechanistic insight into the adaptive biology of SCs, new biomarkers, and a quantitative imaging platform that can be developed to guide the treatment of human schwannoma; they also inform studies of intrinsic heterogeneity in other tumor types. […] Our studies suggest that the ability of Nf2/ SCs to variably enact distinct programs of ErbB ligand production and cytoskeletal polarity upon loss of axonally provided nutrients is a key intrinsic driver of schwannoma heterogeneity. […] Variability in the contribution of these states and their distinct auto/paracrine signaling and metabolic programs to each tumor could underlie the heterogeneous clinical behavior and therapeutic response of schwannomas. […] Our discovery that pS6 is a biomarker of Nrg1 expression but not of mTORC1i sensitivity in cultured Nf2/ SCs, together with the observation that mTORC1i does not block Nrg1 expression itself while ErbBi does, speaks to the complex clinically relevant circuitry that drives the development of these genetically simple tumors.

• #56 Cellular mechanisms of heterogeneity in NF2-mutant schwannoma | Nature Communications

  https://www.nature.com/articles/s41467-023-37226-0

  Schwannomas are common sporadic tumors and hallmarks of familial neurofibromatosis type 2 (NF2) that develop predominantly on cranial and spinal nerves. Virtually all schwannomas result from inactivation of the NF2 tumor suppressor gene with few, if any, cooperating mutations. […] How heterogeneity develops in NF2-mutant schwannomas is unknown. We have found that loss of the membrane:cytoskeleton-associated NF2 tumor suppressor, merlin, yields unstable intrinsic polarity and enables Nf2/ Schwann cells to adopt distinct programs of ErbB ligand production and polarized signaling, suggesting a self-generated model of schwannoma heterogeneity. […] Our studies highlight the importance of intrinsic mechanisms of heterogeneity across human cancers. […] We have found that NF2-deficient SCs exhibit unstable polarity and can adopt distinct phenotypic states featuring coordinated auto/paracrine ErbB ligand and polarity gene expression and polarized cytoskeletal organization, suggesting a model of self-generated heterogeneity that could explain the notoriously variable clinical and therapeutic behaviors of schwannomas.

• #57 Cellular mechanisms of heterogeneity in NF2-mutant schwannoma | Nature Communications

  https://www.nature.com/articles/s41467-023-37226-0

  Our findings provide mechanistic insight into the adaptive biology of SCs, new biomarkers, and a quantitative imaging platform that can be developed to guide the treatment of human schwannoma; they also inform studies of intrinsic heterogeneity in other tumor types. […] Our studies suggest that the ability of Nf2/ SCs to variably enact distinct programs of ErbB ligand production and cytoskeletal polarity upon loss of axonally provided nutrients is a key intrinsic driver of schwannoma heterogeneity. […] Variability in the contribution of these states and their distinct auto/paracrine signaling and metabolic programs to each tumor could underlie the heterogeneous clinical behavior and therapeutic response of schwannomas. […] Our discovery that pS6 is a biomarker of Nrg1 expression but not of mTORC1i sensitivity in cultured Nf2/ SCs, together with the observation that mTORC1i does not block Nrg1 expression itself while ErbBi does, speaks to the complex clinically relevant circuitry that drives the development of these genetically simple tumors.

• #58 NF2: An underestimated player in cancer metabolic reprogramming and tumor immunity | npj Precision Oncology

  https://www.nature.com/articles/s41698-024-00627-5

  The Hippo pathway is implicated in many aspects of tumors, including organ development, tissue regeneration, and epithelial-to-mesenchymal transition (EMT). Merlin negatively regulates the Hippo pathway in the cytoplasm and the nucleus. […] In neurofibromatosis and meningioma, evidence shows that loss of merlin promotes activation of the PI3K-AKT-mTOR pathway, leading to Schwann cell proliferation. […] Several lines of evidence suggest a close relationship between merlin and the rat sarcoma-causing gene (RAS), among which merlin can inhibit the RAS-mediated signalling pathway. […] The first exploration of the relationship between NF2 and Ras could date back to 1994, when Tikoo et al. reported that the overexpression of full-length NF2 could reverse the Ras-induced malignant phenotype. […] Overall, cooccurring deficiencies in BAP1, NF2, and CDKN2A/B might play an instructive role in tumor immunity and are closely related to patient prognosis.

• #59 Neurofibromatosis type 2

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4748851/

  Merlin is a unique tumour suppressor protein because it localises to the cell membranecytoskeletal interface. […] These oncogenic pathways are crucial for promotion of cell growth, protein translation, and cellular proliferation. […] Drugs targeting these pathways (ie, sorafenib, trastuzumab, lapatinib, LY294002, protein kinase inhibitors, and p21-activated kinase inhibitors) and tumour angiogenesis (bevacizumab) are under preclinical or early clinical investigation and are potential treatments for neurofibromatosis type 2.

• #60 Neurofibromatosis Type 2: Current Trends and Future Directions for Targeted Biologic Therapies | IntechOpen

  https://www.intechopen.com/chapters/70156

  Merlin is a multifunctional protein that is involved with the regulation of intra- and extracellular molecules and biologic pathways that are important for cellular structure, survival, proliferation, and contact-dependent inhibition. […] Increased research efforts have enabled the discovery of various molecular pathways and targets relevant to the pathogenesis of NF2-related tumors. […] NF2-VS have increased expression of VEGF, a powerful mediator of tumor angiogenesis. […] Additionally, VS are highly vascular tumors, making anti-angiogenesis an appealing option that has been evaluated in NF2 patients in clinical studies. […] Another growth factor relevant to NF2-pathogenesis is PDGFR. […] The ErbB family of receptor tyrosine kinases has also been increasingly studied in NF2, primarily ErbB1 (EGFR).

• #61 Current Understanding of Neurofibromatosis Type 1, 2, and Schwannomatosis

  https://www.mdpi.com/1422-0067/22/11/5850

  NF2 is caused by a defect in the gene that normally produces merlin, located at 22q12.2 of chromosome 22, which regulates multiple proliferative signaling pathways. At the membrane, merlin blocks signaling caused by integrins and tyrosine receptor kinases. Merlin can also inhibit downstream signalings, including the p21-activated kinase signaling, Ras/Raf/MEK/ERK, FAK/Src, PI3K/AKT, Rac/PAK/JNK, mTORC1, and Wnt/β-catenin pathways. […] The growth of schwannomas requires inactivation of both NF2 alleles. The “second hit” occurs through loss of the entire NF2 gene and most of chromosome 22. Various types of mutations, such as protein-truncating alterations (frameshift deletions/insertions and nonsense mutations), splice-site mutations, missense mutations, are identified. Truncating mutations (nonsense and frameshifts) are the most frequent germline event and cause the most severe disease. […] The NF2 gene product involves multiple molecular pathways in cell growth. Some studies reported on the efficacy of everolimus, an oral inhibitor of the mTORC1, for progressive vestibular schwannomas in NF2 patients.

• #62 Neurofibromatosis Type 2: Current Trends and Future Directions for Targeted Biologic Therapies | IntechOpen

  https://www.intechopen.com/chapters/70156

  Merlin is also involved in regulating a number of pathways and intracellular targets relevant to cellular proliferation and survival. […] In NF2 preclinical studies, loss of merlin activity leads to Schwann cell growth via activation of the PI3K/Akt pathway. […] In addition, gene-expression profiling of sporadic and NF2-associated VS demonstrated overexpression of the PI3K/Akt/mTOR pathway. […] Merlin is considered a negative regulator of mTOR. […] Loss of Merlin function leads to constitutive mTOR signaling in NF2-deficient tumors, including schwannomas, meningiomas, and mesotheliomas. […] In preclinical studies, inhibition with mTORC1 reversed the phenotypic consequences of NF2-deficient schwannoma and meningioma cell lines.

• #63 Neurofibromatosis Type 2: Current Trends and Future Directions for Targeted Biologic Therapies | IntechOpen

  https://www.intechopen.com/chapters/70156

  Merlin is a multifunctional protein that is involved with the regulation of intra- and extracellular molecules and biologic pathways that are important for cellular structure, survival, proliferation, and contact-dependent inhibition. […] Increased research efforts have enabled the discovery of various molecular pathways and targets relevant to the pathogenesis of NF2-related tumors. […] NF2-VS have increased expression of VEGF, a powerful mediator of tumor angiogenesis. […] Additionally, VS are highly vascular tumors, making anti-angiogenesis an appealing option that has been evaluated in NF2 patients in clinical studies. […] Another growth factor relevant to NF2-pathogenesis is PDGFR. […] The ErbB family of receptor tyrosine kinases has also been increasingly studied in NF2, primarily ErbB1 (EGFR).

• #64 Neurofibromatosis: Type 2 | PM&R KnowledgeNow

  https://now.aapmr.org/neurofibromatosis-type-2/

  Genetic testing identifies abnormalities of the NF2 gene on chromosome 22, altering expression of the tumor suppressor merlin. Frame shift and missense mutations are most common in familial cases. […] Targeted therapy agents have been on the horizon for NF2 ongoing preclinical studies and clinical trials for targeted therapies include pharmaceuticals aimed at intervening with cell surface receptors (e.g. epidermal growth factor receptors, platelet-derived growth factors), angiogenesis, and intracellular signaling pathways (e.g. RAF/MEK/ERK, ALK/MET, ALK, mTOR, P21-associated kinases, PI3K/AKT, Heat shock protein 90, COX, NF-kB). In particular, treatment with a vascular endothelial growth factor inhibitor, bevacizumab, has been shown to maintain stable hearing, as well as facilitate tumor reduction and hearing improvement, although use may be limited by potential adverse events.

• #65 Neurofibromatosis Type 2: Current Trends and Future Directions for Targeted Biologic Therapies | IntechOpen

  https://www.intechopen.com/chapters/70156

  Merlin is a multifunctional protein that is involved with the regulation of intra- and extracellular molecules and biologic pathways that are important for cellular structure, survival, proliferation, and contact-dependent inhibition. […] Increased research efforts have enabled the discovery of various molecular pathways and targets relevant to the pathogenesis of NF2-related tumors. […] NF2-VS have increased expression of VEGF, a powerful mediator of tumor angiogenesis. […] Additionally, VS are highly vascular tumors, making anti-angiogenesis an appealing option that has been evaluated in NF2 patients in clinical studies. […] Another growth factor relevant to NF2-pathogenesis is PDGFR. […] The ErbB family of receptor tyrosine kinases has also been increasingly studied in NF2, primarily ErbB1 (EGFR).

• #66 Neurofibromatosis: Type 2 | PM&R KnowledgeNow

  https://now.aapmr.org/neurofibromatosis-type-2/

  Genetic testing identifies abnormalities of the NF2 gene on chromosome 22, altering expression of the tumor suppressor merlin. Frame shift and missense mutations are most common in familial cases. […] Targeted therapy agents have been on the horizon for NF2 ongoing preclinical studies and clinical trials for targeted therapies include pharmaceuticals aimed at intervening with cell surface receptors (e.g. epidermal growth factor receptors, platelet-derived growth factors), angiogenesis, and intracellular signaling pathways (e.g. RAF/MEK/ERK, ALK/MET, ALK, mTOR, P21-associated kinases, PI3K/AKT, Heat shock protein 90, COX, NF-kB). In particular, treatment with a vascular endothelial growth factor inhibitor, bevacizumab, has been shown to maintain stable hearing, as well as facilitate tumor reduction and hearing improvement, although use may be limited by potential adverse events.

• #67

  https://link.springer.com/article/10.1007/s40487-024-00279-2

  Gene therapy for NF2-related schwannomatosis directly supplies a functional copy of the mutated or inactivated NF2 gene to augment functional merlin protein re-expression in NF2-deficient tumor cells to treat the disease phenotype caused by the defective NF2 gene. […] The approach may have a bystander effect, such that transduced schwannoma cells can inhibit the growth of non-transduced cells in the tumor by EV delivery. […] Gene replacement therapy can also be combined with surgical resection and other currently available treatments to achieve potentially synergistic and additive therapeutic effects. […] The gene therapy vector must be efficiently delivered to affected cells in patients to achieve functional expression of targeted genes in specific tissues to treat the disease. […] The gene therapy vectors, which are the key to the success of gene therapy, include viral vectors and non-viral vectors.

• #68 Neurofibromatosis: Type 2 | PM&R KnowledgeNow

  https://now.aapmr.org/neurofibromatosis-type-2/

  An additional gap in NF2 research involves understanding the diseases immune dysregulation. Early studies indicate that NF2 patients exhibit an immunosuppressed state, with elevated cytokine levels and an abundance of immunosuppressive myeloid cells that inhibit anti-tumor responses. This emerging knowledge suggests that targeting these immune cells could lead to novel therapeutic strategies for NF2.

• #69 The genetic landscape and possible therapeutics of neurofibromatosis type 2 | Cancer Cell International | Full Text

  https://cancerci.biomedcentral.com/articles/10.1186/s12935-023-02940-8

  Neurofibromatosis type 2 (NF2) is a genetic condition marked by the development of multiple benign tumors in the nervous system. […] NF2 is caused by loss-of-function mutations in the NF2 gene on chromosome 22, leading the merlin protein to malfunction. […] Recent advances in genetics and molecular biology have allowed identifying and targeting of underlying pathways in the pathogenesis of NF2. […] The advent of molecular biology to scheme the pathogenesis of NF2 can guide to address of new therapeutic potentials for the effective prevention and treatment of NF2-related tumors. […] NF2 is caused by loss of function mutations, deletions, or epigenetic modifications of the NF2 gene (OMIM: 607379). […] Tumorigenesis occurs upon merlin loss of function by modifying downstream signaling pathways.

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

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

  The neurofibromatoses are genetic disorders. NF1 and NF2 are each caused by a mutation in a known specific gene. The quest to understand how these disorders originate and progress (their pathogenesis) received a significant boost when researchers identified the causative genes. The leading theories about the pathogenesis of NF1 and NF2 are discussed in this chapter. […] The search for answers, however, has been daunting. There is probably no single answer to the question, What causes NF1 and NF2? Just as these disorders cause various types of manifestations, so too there appear to be multiple molecular mechanisms at work. […] 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.

• #71 Neurofibromatosis – Wikipedia

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

  Neurofibromatosis type II is caused by a mutation on chromosome 22 (22q12). The mutation falls on the NF2 tumor suppressor gene. The gene normally encodes a cytoplasmic protein known as merlin. The normal function of merlin is to regulate the activity of multiple growth factors, the mutated copy of the gene leads to merlin’s loss of function. The loss of function leads to increased activity of growth factors normally regulated by merlin, leading to the formation of the tumors associated with NF2. […] The pathophysiology is varied, and each NF type has a different one: […] Neurofibromatosis type II is caused by a mutation on chromosome 22 (22q12). The mutation falls on the NF2 tumor suppressor gene. The gene normally encodes a cytoplasmic protein known as merlin. The normal function of merlin is to regulate the activity of multiple growth factors, the mutated copy of the gene leads to merlin’s loss of function. The loss of function leads to increased activity of growth factors normally regulated by merlin, leading to the formation of the tumors associated with NF2.

• #72 Neurofibromatosis Type 2 (NF2) | Encyclopedia MDPI

  https://encyclopedia.pub/entry/7306

  Molecular studies have shown that VS develop as a result of inactivation of both alleles of the NF2 tumor suppressor gene. […] The NF2 gene is located on chromosome 22 at 22q12.2, and codes for the protein Merlin, which has also been called schwannomin. […] Though well-characterized as a tumor suppressor gene, the mechanisms behind Merlin’s tumor suppressor functions have not been fully elucidated.

• #73 The genetic landscape and possible therapeutics of neurofibromatosis type 2 | Cancer Cell International | Full Text

  https://cancerci.biomedcentral.com/articles/10.1186/s12935-023-02940-8

  The types of pathogenic mutations can predict the number of intracranial meningiomas, spinal tumors, and tumors of peripheral nerves. […] The involved site also matters. Mutations in the amino-terminal domain of NF2 proteins are associated with early tumor onset with more severe disease progression. […] The function of ERM proteins is regulated by transitioning between the open and closed states, leading to activation and deactivation of the protein, respectively. […] Merlin regulates cell survival and proliferation in response to multiple proliferative signaling pathways. […] The mechanisms underlying how merlin regulates cell proliferation are yet to be elucidated. […] The inactivation of merlin can lead to uncontrolled cell proliferation and tumorigenesis, especially in the nervous system. […] A comprehensive understanding of molecular mechanisms in tumor progression of NF2-related tumors will provide opportunities for exploring more efficient treatments.

• #74 The genetic landscape and possible therapeutics of neurofibromatosis type 2 | springermedizin.de

  https://www.springermedizin.de/the-genetic-landscape-and-possible-therapeutics-of-neurofibromat/25394884

  The Hippo pathway, an evolutionarily conserved mechanism that controls tissue homeostasis, is one of the most well-known merlin-regulated pathways. […] Comprehensive understanding of molecular mechanisms in tumor progression of NF2-related tumors will provide opportunities for exploring more efficient treatments.

• #75

  https://link.springer.com/article/10.1007/s40487-024-00279-2

  The development of gene therapy for this disease has been greatly impeded by the absence of suitable cell models and animal models. […] Advances in genome-editing methods and organoid technology have opened new avenues for the establishment of preclinical models for NF2-related schwannomatosis gene therapy. […] Gene editing technology is a technique that enables precise modifications to the genome using engineered nucleases. […] The identification of molecular biomarkers in evaluating the efficacy of gene therapy for NF2-related schwannomatosis will improve the efficiency of gene therapy transfer from bench to bedside.

• #76 The genetic landscape and possible therapeutics of neurofibromatosis type 2 | Cancer Cell International | Full Text

  https://cancerci.biomedcentral.com/articles/10.1186/s12935-023-02940-8

  Neurofibromatosis type 2 (NF2) is a genetic condition marked by the development of multiple benign tumors in the nervous system. […] NF2 is caused by loss-of-function mutations in the NF2 gene on chromosome 22, leading the merlin protein to malfunction. […] Recent advances in genetics and molecular biology have allowed identifying and targeting of underlying pathways in the pathogenesis of NF2. […] The advent of molecular biology to scheme the pathogenesis of NF2 can guide to address of new therapeutic potentials for the effective prevention and treatment of NF2-related tumors. […] NF2 is caused by loss of function mutations, deletions, or epigenetic modifications of the NF2 gene (OMIM: 607379). […] Tumorigenesis occurs upon merlin loss of function by modifying downstream signaling pathways.

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