1882 – 1908:

(1) Recklinghausen, F. von. Ueber die multiplen Fibrome der Haut und ihre Beziehung zu den multiplen Neuromen: Festschrift zur Feier des fünfundzwanzigjährigen Bestehens des pathologischen Instituts zu Berlin. Herrn Rudolf Virchow; Hirschwald, 1882. LANDMARK

1. In this first account of neurofibromatosis type I, Friederich Daniel Von Recklinghausen (a German pathologist) described two cases of neurofibromatosis, tumors growing along peripheral nerves. Von Recklinghausen hypothesized that these tumors grew from connective tissue. Furthermore, he described the canonical appearance of the disease.  

(2) Morris, M.; Fox, W. S. Von Recklinghausen’s Disease. Proc. R. Soc. Med. 1908, 1 (Dermatol Sect), 16–17.

1. In this earliest description of neurofibromatosis type I (von Recklinghausen’s Disease), Morris and Fox describe a 42-year-old woman who has had “the condition” since birth and did not experience an increase in tumor size or growth for years. Morris and Fox describe “countless” tumors “all over the body,” and that there were two types: soft subcutaneous masses, and firmer ones, projecting from the surface of the skin. Other than the countless tumors covering her body, Morris and Fox state that the only nervous sign of disease was the patient occasionally fainting.

1908 – 1980:

(3) Alm, I. Primary Tumours of the Optic Nerve and Their Relation to Recklinghausen’s Disease. Acta Paediatr. 1945, 32 (3–4), 262–269. https://doi.org/10.1111/j.1651-2227.1945.tb16821.x. 

1. Up until this point, there has been debate on whether there is a relationship between primary tumors of the optic nerve and NF1, Ingvar is working to clarify the two leading arguments of the time, in this paper. Ingvar describes two patients with tumors of the optic nerve, a 2-year-old girl (who sadly passed away, hours after admission to the hospital), and a 6-year-old boy who was admitted to the hospital due to a sudden difficulty in speaking. The cases presented in this paper support the view that the primary process in NF1 is localized to the nerve cells, with secondary processes resulting in proliferation of tumors in surrounding tissues.

(4) Bader, J. L.; Miller, R. W. Neurofibromatosis and Childhood Leukemia. J. Pediatr. 1978, 92 (6), 925–929. https://doi.org/10.1016/S0022-3476(78)80362-X. LANDMARK

1. To elucidate a potential link between fibromatosis and childhood leukemia, Bader and Miller analyzed 12 novel patient cases. Bader and Miller were able to identify two possible variants of NF-leukemia in this study. The second of the two is a nonlymphocytic leukemia that arises with the appearance of skin xanthomas, an early manifestation of neurofibromatosis.  

1981 – 1989:

(5) Sørensen, S. A.; Mulvihill, J. J.; Nielsen, A. Long-Term Follow-up of von Recklinghausen Neurofibromatosis. N. Engl. J. Med. 1986, 314 (16), 1010–1015. https://doi.org/10.1056/NEJM198604173141603.

1. In this study, Sorensen et al. followed up on a cohort of 212 affected patients and families identified in Denmark in 1946 (42 years before this study was published), in an effort to document the pathogenesis of neurofibromatosis. The development of cancer in the proband group was 2.5%, much greater than the development of cancer for the relatives, additionally females had a greater risk of developing cancer than males. Females also had a significant difference in survival rate between the proband group and the relative group (with the latter being greater). 

(6) Seizinger, B. R.; Martuza, R. L.; Gusella, J. F. Loss of Genes on Chromosome 22 in Tumorigenesis of Human Acoustic Neuroma. Nature 1986, 322 (6080), 644–647. https://doi.org/10.1038/322644a0. LANDMARK *

1. Seizinger et al. used polymorphic DNA markers to search for loss of chromosome regions in acoustic neuromas from the leukocytes and primary acoustic neuromas of 21 patients. By probing chromosome 22, Seizinger et al. found that sixteen patients were heterozygous for at least one of the three polymorphic DNA markers on chromosome 22. Based on this analysis, Seizinger et al. were able to conclude that acoustic neuromas specifically lose genes on chromosome 22, suggesting that similar mechanisms govern the development of acoustic neuromas and meningiomas (both of which occur frequently in neurofibromatosis). 

(7) Seizinger, B. R.; Rouleau, G. A.; Ozelius, L. J.; Lane, A. H.; Faryniarz, A. G.; Chao, M. V.; Huson, S.; Korf, B. R.; Parry, D. M.; Pericak-Vance, M. A.; Collins, F. S.; Hobbs, W. J.; Falcone, B. G.; Iannazzi, J. A.; Roy, J. C.; St George-Hyslop, P. H.; Tanzi, R. E.; Bothwell, M. A.; Upadhyaya, M.; Harper, P.; Goldstein, A. E.; Hoover, D. L.; Bader, J. L.; Spence, M. A.; Mulvihill, J. J.; Aylsworth, A. S.; Vance, J. M.; Rossenwasser, G. O. D.; Gaskell, P. C.; Roses, A. D.; Martuza, R. L.; Breakefield, X. O.; Gusella, J. F. Genetic Linkage of von Recklinghausen Neurofibromatosis to the Nerve Growth Factor Receptor Gene. Cell 1987, 49 (5), 589–594. https://doi.org/10.1016/0092-8674(87)90534-4. *

1. With the advent of recombinant DNA techniques, Seizinger et al. worked to find the chromosomal location of the gene responsible for NF in order to begin isolating and characterizing the relevant genetic defect. Seizinger et al. propose three hypotheses to explain the unexplainably high rate of new mutations in NF – a large size of the NF gene, nonallelic heterogeneity, and that NF is caused by two very tightly linked mutations that must be present on the same chromosome.  More conclusively, the NF gene was found to be linked to a locus on chromosome 17 encoding the receptor for nerve growth factor. This study opens up significant potential for the prospects gained via isolation of the NF gene.  

(8) Seizinger, R.; Rouleau, G.; Ozelius, A.; Lane, A.; George-Hyslop, P.; Huson, S.; Gusella, J.; Martuza, R. Common Pathogenetic Mechanism for Three Tumor Types in Bilateral Acoustic Neurofibromatosis. Science 1987, 236, 317-319. https://www.science.org/doi/abs/10.1126/science.3105060  (accessed 2022 -03 -11). *

1. In this paper, Seizinger et al. work to uncover the biochemical defect leading to the development of tumors in patients with bilateral acoustic neurofibromatosis (BANF). Seizinger et al. analyzed DNA from tumor tissue and lymphocytes from patients with BANF and used polymorphic DNA markers for chromosome 22 to detect the loss of chromosome 22 sequences (since their previous report uncovered that the specific loss of genes on chromosome 22 occurs frequently in neuroma cases). Their polymorphic DNA analysis highlighted the high frequency of chromosome 22 gene loss in heritable forms of neurofibromatosis (BANF, in this case). Therefore, a gene on chromosome 22 is either responsible for BANF, or the loss of genes on chromosome 22 may be due to the loss of the BANF gene on another chromosome.  

(9) Madigan, P.; Shaw, R. V. Neurofibromatosis in 13th Century Austria? Neurofibromatosis 1988, 1 (5–6), 339–341.

(10) Madigan, P.; Masello, M. J. Report of a Neurofibromatosis-like Case: Monstrorum Historia, 1642. Neurofibromatosis 1989, 2 (1), 53–56.

1990 – 1999:

(11) Cawthon, Richard M., W., Robert; Xu, G.; Viskochil, D.; Culver, M.; Stevens, J.; Roberston, M.; Dunn, D.; Gesteland, R.; O’Connell, P.; White, R. A Major Segment of the Neurofibromatosis Type 1 Gene: CDNA Sequence, Genomic Structure, and Point Mutations. Cell 1990, 62, 193–201. DOI: 10.1016/0092-8674(90)90253-b  LANDMARK *

1. Recent studies have implicated the translocation breakpoint region (TBR) gene as the NF1-causing gene. Cawthon et al. are testing this hypothesis by comparing a cDNA sequence from previously identified clones with genomic DNA sequences. It was confirmed that the TBR gene is the gene for NF1. 6 base pair variants were found among 72 NF1 patients, and did not appear in the control group. 

(12) Xu, G.; O’Connell, P.; Viskochil, D.; Cawthon, Richard M.; Roberston, M.; Culver, M.; Dunn, D.; Stevens, J.; Gesteland, R.; White, R.; Weiss, R. The Neurofibramotosis Type 1 Gene Encodes a Protein Related to GAP. Cell 1990, 62, 559–608. doi: 10.1016/0092-8674(90)90024-9. LANDMARK *

1. Xu et al. describe three novel NF-1 deletion mutations and two new NF-1 specific point mutations impacting the NF1 gene. By analyzing the 5’ ends of cDNA clones, Xu et al. were able to determine that NF1 is interrupted by a t(1;17) translocation that causes NF1. This finding confirms previous reports that the three genes that map between the NF1 translocation breakpoints are in an intron of the NF1 gene.

(13) Martin, G.; Viskochil, D.; Bollag, G.; McCabe, P.; Crosier, W.; Haubruck, H.; Conroy, L.; Clark, R.; O’Connell, P.; Cawthon, Richard M.; Innis, M.; McCormick, F. The GAP-Related Domain of the Neurofibromatosis Type 1 Gene Products Interacts with Ras P21. 1990, 63, 843–849. https://doi.org/10.1016/0092-8674(90)90150-D  LANDMARK *

1. A gene implicated in NF1 was found to have 30% similarity with the catalytic domains for yeast IRA proteins and mammalian GAP proteins, raising the question of whether the NF1 protein interacts with ras p21 activity. It was found that NF1 stimulates the GTPase activity of canonical ras p21, but not the oncogenic mutants. A correlation between NF1 and ras p21 exists, but the mechanism of this relationship remains unclear. 

(14) Wallace, M. R.; Andersen, L. B.; Saulino, A. M.; Gregory, P. E.; Glover, T. W.; Collins, F. S. A de Novo Alu Insertion Results in Neurofibromatosis Type 1. Nature 1991, 353 (6347), 864–866. https://doi.org/10.1038/353864a0. 

1. Wallace et al. studied the genetic profile of a 31-year old male patient with NF1, as well as the genetic profile of his parents. Upon Southern Blot analysis, an Alu repetitive element was found in exon number 6 of the patient. Exon number 6 of the parents was normal. This repetitive element led to the deletion of a downstream exon during splicing. It is thought that this mutation arose by retrotransposition in the father’s germline, or an insertion into the paternal chromosome during early embryogenesis (the latter being less likely). 

(15) Zöller, M. E. T.; Rembeck, B.; Odén, A.; Samuelsson, M.; Angervall, L. Malignant and benign tumors in patients with neurofibromatosis type 1 in a defined Swedish population. Cancer 1997, 79 (11), 2125–2131. https://doi.org/10.1002/(SICI)1097-0142(19970601)79:11<2125::AID-CNCR9>3.0.CO;2-N. 

1. A population in Goteborg, Sweden, has been used for long term NF1 follow-up due to the high prevalence of NF1 in the population. Zoller et al. used this cohort to estimate the risk of developing malignancies in adult NF1 patients and to determine why types of tumors developed in the NF1 patients. The authors were able to define a 12-year interval in adulthood that NF1 patients were significantly more at risk to develop malignant tumors such as soft tissue sarcoma.

(16) Structural analysis of the GAP‐related domain from neurofibromin and its implications https://www.embopress.org/doi/epdf/10.1093/emboj/17.15.4313 (accessed 2022 -04 -16). https://doi.org/10.1093/emboj/17.15.4313.

(17) Cichowski, K.; Shih, T. S.; Schmitt, E.; Santiago, S.; Reilly, K.; McLaughlin, M. E.; Bronson, R. T.; Jacks, T. Mouse Models of Tumor Development in Neurofibromatosis Type 1. Science 1999, 286 (5447), 2172–2176. https://doi.org/10.1126/science.286.5447.2172. *

1. Cichowski et al. used transgenic mice to test the hypothesis that a mutation in the wild-type Nf1 gene allele is required to form neurofibromas. The group found that the complete loss of the Nf1 gene is required for the development of neurofibromas. Furthermore, the development of malignant peripheral nerve sheath tumors (MPNSTs) was dependent on mutations in Nf1 and p53.  

2000 – 2009:

(18) Rutkowski, J. L.; Wu, K.; Gutmann, D. H.; Boyer, P. J.; Legius, E. Genetic and Cellular Defects Contributing to Benign Tumor Formation in Neurofibromatosis Type 1. Hum. Mol. Genet. 2000, 9 (7), 1059–1066. https://doi.org/10.1093/hmg/9.7.1059. 

1. It is thought that NF1 arises due to inactivation of the NF1 gene in S100⁺ Schwann cells, Rutkowski et al. are seeking to clarify the pattern of NF1 allele inactivation in Schwann cells leading to NF1. S100⁺ cells isolated from neurofibromas completely lacked NF1 mRNA, providing the first molecular evidence that S100⁺ cells are both primarily responsible for the pathogenesis of neurofibromas, and that they carry an NF1 defect. Though NF1 gene activation was essential for NF1-associated tumor formation, the variations in defective cells suggest that additional mechanisms are responsible for the determination of NF1 pathology.  

(19) Ars, E.; Serra, E.; García, J.; Kruyer, H.; Gaona, A.; Lázaro, C.; Estivill, X. Mutations Affecting MRNA Splicing Are the Most Common Molecular Defects in Patients with Neurofibromatosis Type 1. Hum. Mol. Genet. 2000, 9 (2), 237–247. https://doi.org/10.1093/hmg/9.2.237. *

1. In this paper, Ars et al. seek to extend the NF1-associated gene mutation to the mRNA levels, as current understanding of the molecular pathogenesis of the disease revolves around protein truncation. Ars et al. performed reverse transcription and amplification of the NF1 coding region and a mutant analysis of 80 unrelated NF1 patients. Most of the mutations found led to errors in the splicing of NF1 mRNA, leading to NF1 proteins being abnormally sized in 94% of patients. However, coupling their genomic data with clinical information, Ares et al. found that location and type of genomic mutations has no relationship to clinical disease, indicating that modifier genes may have an important role in NF1. 

(20) Costa, R. M.; Federov, N. B.; Kogan, J. H.; Murphy, G. G.; Stern, J.; Ohno, M.; Kucherlapati, R.; Jacks, T.; Silva, A. J. Mechanism for the Learning Deficits in a Mouse Model of Neurofibromatosis Type 1. Nature 2002, 415 (6871), 526–530. https://doi.org/10.1038/nature711. LANDMARK *

1. Patients with NF1 report that visual-spatial problems ae the most common cognitive defect, which parallels mice induced with NF1. Costa et al. are testing the hypothesis that this deficit is due to an upregulation of Ras activity by crossing mice with an NF1 mutation, and mice with a Ras mutation. Costa et al. found that abnormally high or low Ras activity can disrupt learning, and that reducing Ras levels pharmacologically was found to reverse the learning deficits associated with NF1.  

(21) Fahsold, R.; Habash, T.; Trautmann, U.; Haustein, A.; Pfeiffer, R. Familial Reciprocal Translocation t(17;19) (Q11.2;Q13.2) Associated with Neurofibromatosis Type 1, Including One Patient with Non-Hodgkin Lymphoma and an Additional t(14;20) in B Lymphocytes. Hum. Genet. 2004. https://doi.org/10.1007/BF00214188.

(22) A Novel Bipartite Phospholipid-Binding Module in the Neurofibromatosis Type 1 Protein. EMBO Rep. 2006, 7 (2), 174–179. https://doi.org/10.1038/sj.embor.7400602.

(23) Boyd, K. P.; Korf, B. R.; Theos, A. Neurofibromatosis Type 1. J. Am. Acad. Dermatol. 2009, 61 (1), 1–14. https://doi.org/10.1016/j.jaad.2008.12.051.(7) Diagnosing Neurofibromatosis https://nyulangone.org/conditions/neurofibromatosis/diagnosis (accessed 2022 -04 -25).

(24) Gilfillan, A. M.; Rivera, J. The Tyrosine Kinase Network Regulating Mast Cell Activation. Immunol. Rev. 2009, 228 (1), 149–169. https://doi.org/10.1111/j.1600-065X.2008.00742.x.

(25) AboutKidsHealth https://www.aboutkidshealth.ca:443/article?contentid=866&language=english (accessed 2022 -04 -26).

2011 – Present:

(26) Legendre, C.-M.; Charpentier-Côté, C.; Drouin, R.; Bouffard, C. Neurofibromatosis Type 1: Persisting Misidentification of the “Elephant Man” Disease. J. Am. Board Fam. Med. 2011, 24 (1), 112–114. https://doi.org/10.3122/jabfm.2011.01.100219.

(27) Terzi, Y. K.; Sirin, B.; Hosgor, G.; Serdaroglu, E.; Anlar, B.; Aysun, S.; Ayter, S. Two Pathogenic NF1 Gene Mutations Identified in DNA from a Child with Mild Phenotype. Childs Nerv. Syst. 2012, 28 (6), 943–946. https://doi.org/10.1007/s00381-011-1648-x. *

1. Due to the phenotypic variability in NF1 patients with similar mutations in the NF1 gene, Terzi et al. are studying a family with NF1 due to a deletion in exon 17 and an insertion in exon 29 of the NF1 gene. In the studied family, the daughter and father both presented with NF1 and a deletion in exon 17, but the daughter had a novel mutation in exon 29 that led to the synthesis of a prematurely truncated NF protein. Though the daughter had two pathogenic mutations, her clinical presentation was relatively benign, potentially due to the importance of modifier genes in NF1, or the location of the mutations. The homogeneity of the NF1 gene between the father and daughter provides greater merit for the hypothesis that NF1 mutations are transmitted paternally, but the presentation of a novel mutation in the daughter underscores the importance of comprehensive genetic testing for NF1, as most laboratories stop sequencing after one NF1 mutation is identified. 

(28) Putney, J. W.; Tomita, T. Phospholipase C Signaling and Calcium Influx. Adv. Biol. Regul. 2012, 52 (1), 152–164. https://doi.org/10.1016/j.advenzreg.2011.09.005.

(29) Lyon, A. M.; Tesmer, J. J. G. Structural Insights into Phospholipase C-β Function. Mol. Pharmacol. 2013, 84 (4), 488–500. https://doi.org/10.1124/mol.113.087403.

(30) Blatty, D. Joseph Merrick https://www.biography.com/performer/elephant-man-joseph-merrick (accessed 2022 -03 -27).

(31) Hillmer, E. J.; Zhang, H.; Li, H. S.; Watowich, S. S. STAT3 Signaling in Immunity. Cytokine Growth Factor Rev. 2016, 31, 1–15. https://doi.org/10.1016/j.cytogfr.2016.05.001.

(32) Krystel-Whittemore, M.; Dileepan, K. N.; Wood, J. G. Mast Cell: A Multi-Functional Master Cell. Front. Immunol. 2016, 6.

(33) Dombi, E.; Baldwin, A.; Marcus, L. J.; Fisher, M. J.; Weiss, B.; Kim, A.; Whitcomb, P.; Martin, S.; Aschbacher-Smith, L. E.; Rizvi, T. A.; Wu, J.; Ershler, R.; Wolters, P.; Therrien, J.; Glod, J.; Belasco, J. B.; Schorry, E.; Brofferio, A.; Starosta, A. J.; Gillespie, A.; Doyle, A. L.; Ratner, N.; Widemann, B. C. Activity of Selumetinib in Neurofibromatosis Type 1–Related Plexiform Neurofibromas. N. Engl. J. Med. 2016, 375 (26), 2550–2560. https://doi.org/10.1056/NEJMoa1605943. LANDMARK

1. The NF1 product, neurofibromin, functions as a negative regulator of RAS activity. In mouse models of neurofibromatosis type 1, MAPK inhibition induced tumor regression, therefore, the oral selective inhibitor of MEK 1 and 2, selumetinib, was tested on children with neurofibromatosis type 1 as a phase 1 trial. All patients in the trial experienced a decrease in tumor volume, and there was a slow tumor regrowth in several patients (most of whom had to reduce their dosage due to toxicity), indicating a dose-dependent effect of MEK inhibition on the growth of neurofibromatosis-related tumors. 

(34) Phospholipase Cγ in Toll-like receptor-mediated inflammation and innate immunity – ScienceDirect https://www-sciencedirect-com.muhlenberg.idm.oclc.org/science/article/pii/S221249261630032X?via%3Dihub (accessed 2022 -04 -15).

(35) Liao, C.-P.; Booker, R. C.; Brosseau, J.-P.; Chen, Z.; Mo, J.; Tchegnon, E.; Wang, Y.; Clapp, D. W.; Le, L. Q. Contributions of Inflammation and Tumor Microenvironment to Neurofibroma Tumorigenesis. J. Clin. Invest. 128 (7), 2848–2861. https://doi.org/10.1172/JCI99424.

(36) Fletcher, J. S.; Springer, M. G.; Choi, K.; Jousma, E.; Rizvi, T. A.; Dombi, E.; Kim, M.-O.; Wu, J.; Ratner, N. STAT3 Inhibition Reduces Macrophage Number and Tumor Growth in Neurofibroma. Oncogene 2019, 38 (15), 2876–2884. https://doi.org/10.1038/s41388-018-0600-x. *

1. Plexiform neurofibromas are associated with the onset of NF1, and Fletcher et al. are working to show the regulatory mechanisms governing the development of plexiform neurofibromas. STAT3 was found to be key for permitting the growth of established neurofibromas, regulating cytokine expression in neurofibromas, and crucial for the expression of macrophage-recruiting chemokines. Therefore, STAT3 is a key regulator of the neurofibroma inflammatory microenvironment.

(37) Assunto, A.; Ferrara, U.; De Luca, A.; Pivonello, C.; Lombardo, L.; Piscitelli, A.; Tortora, C.; Pinna, V.; Daniele, P.; Pivonello, R.; Russo, M.; Limongelli, G.; Colao, A.; Tartaglia, M.; Strisciuglio, P.; Melis, D. Isoform-specific NF1 mRNA levels correlate with disease severity in Neurofibromatosis type 1 | Orphanet Journal of Rare Diseases 2019, 14| Full Text https://ojrd.biomedcentral.com/articles/10.1186/s13023-019-1223-1  (accessed 2022 -03 -09). 

1. NF1 cannot be explained solely by pathogenic NF1 gene mutations, therefore, Assunto et al. performed qPCR to investigate the hypothesis that variations in protein isoform levels contribute to phenotypic variability. The researchers found an inverse correlation between the severity of NF1 phenotype and the levels of isoform I mRNA. This finding provides evidence for the importance of NF1 transcript processing in determining NF1 expressivity and phenotype severity.

(38) Gorelick, K. Inheritance and Genetics of Neurofibromatosis Type 1 (NF1) – School of Medicine – Neurofibromatosis Program | UAB https://www.uab.edu/medicine/nfprogram/learn/neurofibromatosis-type-1-nf1/inheritance-genetics (accessed 2022 -04 -24).

(39) Xu, J.; Zhang, H.; Li, C.; Du, H.; Shu, M.; Shu, M. Activation of PLCγ/AKT/IκBα/p65 signaling increases inflammation in mast cells to promote growth of cutaneous neurofibroma. Life Sciences 2019, 239 https://www-sciencedirect-com.muhlenberg.idm.oclc.org/science/article/pii/S0024320519310069?via%3Dihub  (accessed 2022 -03 -09). *

1. In this paper, Xu et al. elucidated the underlying mechanism between a hallmark feature of NF1, cutaneous neurofibromas (cNF), and mast cells. The PI3K/AKT/p-IᴋB𝝰/p65 signaling pathway was found to be crucial for mast cell inflammation, opening up promising therapeutic potential in reducing cNF cell growth. Furthermore, this signaling pathway was found to be significantly repressed (through the inflammatory activity of mast cells) upon inhibition of PLCᵧ. 

(40) Neurofibromin Structure, Functions and Regulation – PMC https://www-ncbi-nlm-nih-gov.muhlenberg.idm.oclc.org/pmc/articles/PMC7692384/ (accessed 2022 -04 -15).

(41) Guo, Y.-J.; Pan, W.-W.; Liu, S.-B.; Shen, Z.-F.; Xu, Y.; Hu, L.-L. ERK/MAPK Signalling Pathway and Tumorigenesis (Review). Exp. Ther. Med. 2020, 19 (3), 1997–2007. https://doi.org/10.3892/etm.2020.8454.

(42) Gonzalez, L. L.; Garrie, K.; Turner, M. D. Role of S100 Proteins in Health and Disease. Biochim. Biophys. Acta BBA – Mol. Cell Res. 2020, 1867 (6), 118677. https://doi.org/10.1016/j.bbamcr.2020.118677.

(43) Tamura, R. Current Understanding of Neurofibromatosis Type 1, 2, and Schwannomatosis. Int. J. Mol. Sci. 2021, 22 (11), 5850. https://doi.org/10.3390/ijms22115850.

(44) Park, G.-H.; Lee, S.-J.; Lee, C.-G.; Kim, J.; Park, E.; Jeong, S.-Y. Neurofibromin Deficiency Causes Epidermal Growth Factor Receptor Upregulation through the Activation of Ras/ERK/SP1 Signaling Pathway in Neurofibromatosis Type 1-Associated Malignant Peripheral Nerve Sheet Tumor. Int. J. Mol. Sci. 2021, 22 (24), 13308. https://doi.org/10.3390/ijms222413308. *

1. It is known that elevated epidermal growth factor receptor (EGFR) expression is integral to the progression of plexiform neurofibromas to malignant peripheral nerve sheet tumors (MPNSTs), in this paper, Park et al. attempt to uncover the determinants of EGFR overexpression. Through the use of tissue specimens of NF1, Park et al. found an inversion relationship between the amount of neurofibromin and EGFR expression. Park et al elucidated the molecular mechanism of this relationship, as well: loss of neurofibromin led to increased activation of the Ras/ERK signaling pathway, enhancing activated SP1 translocation from the cytosol to the nucleus and binding to EGFR promoter regions, leading to the transcription of EGFR. 

(45) Tritz, R.; Hudson, F. Z.; Harris, V.; Ghoshal, P.; Singla, B.; Lin, H.; Csanyi, G.; Stansfield, B. K. MEK Inhibition Exerts Temporal and Myeloid Cell-Specific Effects in the Pathogenesis of Neurofibromatosis Type 1 Arteriopathy. Sci. Rep. 2021, 11 (1), 24345. https://doi.org/10.1038/s41598-021-03750-6. *

1. In this study, Tritz et al. are seeking to determine the relationship between MEK activation and immune cell function in the pathogenesis of NF1’s deleterious effects on the arteries. The loss of neurofibromin led to the enhancement of neutrophil activity through MEK-ERK signaling. This finding, in addition to the others throughout this paper, led to the conclusion that inactivating mutations in the NF1 gene allowed for the cells to survive using Ras-MEK signaling, indicating the need for cell-specific therapeutic approaches for patients with NF1 due to the complexity of cell interactions governing the pathogenesis of the disease. 

(46) Lupton, C. J.; Bayly-Jones, C.; D’Andrea, L.; Huang, C.; Schittenhelm, R. B.; Venugopal, H.; Whisstock, J. C.; Halls, M. L.; Ellisdon, A. M. The Cryo-EM Structure of the Human Neurofibromin Dimer Reveals the Molecular Basis for Neurofibromatosis Type 1. Nat. Struct. Mol. Biol. 2021, 28 (12), 982–988. https://doi.org/10.1038/s41594-021-00687-2. *In this paper, Lupton et al. used a cryo-electron microscope to determine the structure of the NF1 homodimer to better understand the function of the protein. Lupton et al. uncovered the five interfaces governing NF1 dimer assembly, the location of the catalytic domain when the homodimer is in the “closed” conformation, as well as analyzed neurofibromatosis type 1 and cancer-associated mutations in terms of structure (and therefore, with a potential extrapolation to function). Lupton et al. elucidated the importance of the complex core scaffold of the homodimer to the susceptibility of the NF1 gene for mutations. Lupton et al. propose that stabilization of the open conformation may prevent loss-of-function of the NF1 protein.

(47) Neurofibromatosis (NF1 and NF2) https://weillcornellbrainandspine.org/condition/neurofibromatosis-nf1-and-nf2 (accessed 2022 -04 -24).

(48) Fallon, M.; Tadi, P. Histology, Schwann Cells. In StatPearls; StatPearls Publishing: Treasure Island (FL), 2022.