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Neurofibromin and suppression of tumorigenesis: beyond the GAP

Oncogene volume 41, pages 1235–1251 (2022)Cite this article

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Abstract

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disease and one of the most common inherited tumor predisposition syndromes, affecting 1 in 3000 individuals worldwide. The NF1 gene encodes neurofibromin, a large protein with RAS GTP-ase activating (RAS-GAP) activity, and loss of NF1 results in increased RAS signaling. Neurofibromin contains many other domains, and there is considerable evidence that these domains play a role in some manifestations of NF1. Investigating the role of these domains as well as the various signaling pathways that neurofibromin regulates and interacts with will provide a better understanding of how neurofibromin acts to suppress tumor development and potentially open new therapeutic avenues. In this review, we discuss what is known about the structure of neurofibromin, its interactions with other proteins and signaling pathways, its role in development and differentiation, and its function as a tumor suppressor. Finally, we discuss the latest research on potential therapeutics for neurofibromin-deficient neoplasms.

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Fig. 1: Diagram of the clinical manifestations of NF1.
Fig. 2: Domains of the neurofibromin protein and proteins that directly interact with those domains.
Fig. 3: Downstream signaling of NF1: molecular functions of neurofibromin in key biological signaling pathways.
Fig. 4: Clinical manifestations of NF1.
Fig. 5: NF1 genotype-phenotype correlations.
Fig. 6: List of sporadic tumors with NF1 mutation.

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References

  1. Friedman, JM, Neurofibromatosis 1, in GeneReviews((R)), Adam MP, et al., editors. Seattle (WA):GeneReviews;1993.

  2. Le LQ, Parada LF. Tumor microenvironment and neurofibromatosis type I: connecting the GAPs. Oncogene. 2007;26:4609–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Evans DG, Baser ME, McGaughran J, Sharif S, Howard E, Moran A. Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J Med Genet. 2002;39:311–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Mautner VF, Friedrich RE, von Deimling A, Hagel C, Korf B, Knofel MT, et al. Malignant peripheral nerve sheath tumours in neurofibromatosis type 1: MRI supports the diagnosis of malignant plexiform neurofibroma. Neuroradiology. 2003;45:618–25.

    Article  CAS  PubMed  Google Scholar 

  5. Ballester R, Marchuk D, Boguski M, Saulino A, Letcher R, Wigler M, et al. The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins. Cell. 1990;63:851–9.

    Article  CAS  PubMed  Google Scholar 

  6. Martin GA, Viskochil D, Bollag G, McCabe PC, Crosier WJ, Haubruck H, et al. The GAP-related domain of the neurofibromatosis type 1 gene product interacts with ras p21. Cell. 1990;63:843–9.

    Article  CAS  PubMed  Google Scholar 

  7. Daston MM, Scrable H, Nordlund M, Sturbaum AK, Nissen LM, Ratner N. The protein product of the neurofibromatosis type 1 gene is expressed at highest abundance in neurons, Schwann cells, and oligodendrocytes. Neuron. 1992;8:415–28.

    Article  CAS  PubMed  Google Scholar 

  8. Gutmann DH, Wood DL, Collins FS. Identification of the neurofibromatosis type 1 gene product. Proc Natl Acad Sci USA. 1991;88:9658–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Izawa I, Tamaki N, Saya H. Phosphorylation of neurofibromatosis type 1 gene product (neurofibromin) by cAMP-dependent protein kinase. FEBS Lett. 1996;382:53–9.

    Article  CAS  PubMed  Google Scholar 

  10. Barron VA, Lou H. Alternative splicing of the neurofibromatosis type I pre-mRNA. Biosci Rep. 2012;32:131–8.

    Article  CAS  PubMed  Google Scholar 

  11. Larizza L, Gervasini C, Natacci F, Riva P. Developmental abnormalities and cancer predisposition in neurofibromatosis type 1. Curr Mol Med. 2009;9:634–53.

    Article  CAS  PubMed  Google Scholar 

  12. Xu M, Xiong H, Han Y, Li C, Mai S, Huang Z, et al. Identification of Mutation Regions on NF1 Responsible for High- and Low-Risk Development of Optic Pathway Glioma in Neurofibromatosis Type I. Front Genet. 2018;9:270.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Gregory PE, Gutmann DH, Mitchell A, Park S, Boguski M, Jacks T, et al. Neurofibromatosis type 1 gene product (neurofibromin) associates with microtubules. Somat Cell Mol Genet. 1993;19:265–74.

    Article  CAS  PubMed  Google Scholar 

  14. Sherekar M, Han SW, Ghirlando R, Messing S, Drew M, Rabara D, et al. Biochemical and structural analyses reveal that the tumor suppressor neurofibromin (NF1) forms a high-affinity dimer. J Biol Chem. 2020;295:1105–19.

    Article  PubMed  Google Scholar 

  15. Bollag G, McCormick F, Clark R. Characterization of full-length neurofibromin: tubulin inhibits Ras GAP activity. EMBO J. 1993;12:1923–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Arun V, Worrell L, Wiley JC, Kaplan DR, Guha A. Neurofibromin interacts with the cytoplasmic Dynein Heavy Chain 1 in melanosomes of human melanocytes. FEBS Lett. 2013;587:1466–73.

    Article  CAS  PubMed  Google Scholar 

  17. Arun V, Wiley JC, Kaur H, Kaplan DR, Guha A. A novel neurofibromin (NF1) interaction with the leucine-rich pentatricopeptide repeat motif-containing protein links neurofibromatosis type 1 and the French Canadian variant of Leigh’s syndrome in a common molecular complex. J Neurosci Res. 2013;91:494–505.

    Article  CAS  PubMed  Google Scholar 

  18. Anastasaki C, Le LQ, Kesterson RA, Gutmann DH. Updated nomenclature for human and mouse neurofibromatosis type 1 genes. Neurol Genet. 2017;3:e169.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Jessen WJ, Miller SJ, Jousma E, Wu J, Rizvi TA, Brundage ME, et al. MEK inhibition exhibits efficacy in human and mouse neurofibromatosis tumors. J Clin Investig. 2013;123:340–7.

    Article  CAS  PubMed  Google Scholar 

  20. Dasgupta B, Yi Y, Chen DY, Weber JD, Gutmann DH. Proteomic analysis reveals hyperactivation of the mammalian target of rapamycin pathway in neurofibromatosis 1-associated human and mouse brain tumors. Cancer Res. 2005;65:2755–60.

    Article  CAS  PubMed  Google Scholar 

  21. Johannessen CM, Reczek EE, James MF, Brems H, Legius E, Cichowski K. The NF1 tumor suppressor critically regulates TSC2 and mTOR. Proc Natl Acad Sci USA. 2005;102:8573–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Cui Y, Costa RM, Murphy GG, Elgersma Y, Zhu Y, Gutmann DH, et al. Neurofibromin regulation of ERK signaling modulates GABA release and learning. Cell. 2008;135:549–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Chen YH, Gianino SM, Gutmann DH. Neurofibromatosis-1 regulation of neural stem cell proliferation and multilineage differentiation operates through distinct RAS effector pathways. Genes Dev. 2015;29:1677–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Sanchez-Ortiz E, Cho W, Nazarenko I, Mo W, Chen J, Parada LF. NF1 regulation of RAS/ERK signaling is required for appropriate granule neuron progenitor expansion and migration in cerebellar development. Genes Dev. 2014;28:2407–20.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. De Schepper S, Boucneau JM, Westbroek W, Mommaas M, Onderwater J, Messiaen L, et al. Neurofibromatosis type 1 protein and amyloid precursor protein interact in normal human melanocytes and colocalize with melanosomes. J Invest Dermatol. 2006;126:653–9.

    Article  PubMed  CAS  Google Scholar 

  26. Bausch B, Borozdin W, Mautner VF, Hoffmann MM, Boehm D, Robledo M, et al. Germline NF1 mutational spectra and loss-of-heterozygosity analyses in patients with pheochromocytoma and neurofibromatosis type 1. J Clin Endocrinol Metab. 2007;92:2784–92.

    Article  CAS  PubMed  Google Scholar 

  27. Dunzendorfer-Matt T, Mercado EL, Maly K, McCormick F, Scheffzek K. The neurofibromin recruitment factor Spred1 binds to the GAP related domain without affecting Ras inactivation. Proc Natl Acad Sci USA. 2016;113:7497–502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hirata Y, Brems H, Suzuki M, Kanamori M, Okada M, Morita R, et al. Interaction between a Domain of the Negative Regulator of the Ras-ERK Pathway, SPRED1 Protein, and the GTPase-activating Protein-related Domain of Neurofibromin Is Implicated in Legius Syndrome and Neurofibromatosis Type 1. J Biol Chem. 2016;291:3124–34.

    Article  CAS  PubMed  Google Scholar 

  29. Stowe IB, Mercado EL, Stowe TR, Bell EL, Oses-Prieto JA, Hernandez H, et al. A shared molecular mechanism underlies the human rasopathies Legius syndrome and Neurofibromatosis-1. Genes Dev. 2012;26:1421–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Moutal A, Wang Y, Yang X, Ji Y, Luo S, Dorame A, et al. Dissecting the role of the CRMP2-neurofibromin complex on pain behaviors. Pain. 2017;158:2203–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hsueh YP, Roberts AM, Volta M, Sheng M, Roberts RG. Bipartite interaction between neurofibromatosis type I protein (neurofibromin) and syndecan transmembrane heparan sulfate proteoglycans. J Neurosci. 2001;21:3764–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Aravind L, Neuwald AF, Ponting CP. Sec14p-like domains in NF1 and Dbl-like proteins indicate lipid regulation of Ras and Rho signaling. Curr Biol. 1999;9:R195–197.

    Article  CAS  PubMed  Google Scholar 

  33. D’Angelo I, Welti S, Bonneau F, Scheffzek K. A novel bipartite phospholipid-binding module in the neurofibromatosis type 1 protein. EMBO Rep. 2006;7:174–9.

    Article  PubMed  CAS  Google Scholar 

  34. Fadhlullah SFB, Halim NBA, Yeo JYT, Ho RLY, Um P, Ang BT, et al. Pathogenic mutations in neurofibromin identifies a leucine-rich domain regulating glioma cell invasiveness. Oncogene. 2019;38:5367–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wang HF, Shih YT, Chen CY, Chao HW, Lee MJ, Hsueh YP. Valosin-containing protein and neurofibromin interact to regulate dendritic spine density. J Clin Investig. 2011;121:4820–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Boyanapalli M, Lahoud OB, Messiaen L, Kim B, Anderle de Sylor MS, Duckett SJ, et al. Neurofibromin binds to caveolin-1 and regulates ras, FAK, and Akt. Biochem Biophys Res Commun. 2006;340:1200–8.

    Article  CAS  PubMed  Google Scholar 

  37. Deraredj Nadim W, Chaumont-Dubel S, Madouri F, Cobret L, De Tauzia ML, Zajdel P, et al. Physical interaction between neurofibromin and serotonin 5-HT6 receptor promotes receptor constitutive activity. Proc Natl Acad Sci USA. 2016;113:12310–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Vallee B, Doudeau M, Godin F, Gombault A, Tchalikian A, de Tauzia ML, et al. Nf1 RasGAP inhibition of LIMK2 mediates a new cross-talk between Ras and Rho pathways. PLoS One. 2012;7:e47283.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Melloni G, Eoli M, Cesaretti C, Bianchessi D, Ibba MC, Esposito S, et al. Risk of Optic Pathway Glioma in Neurofibromatosis Type 1: No Evidence of Genotype-Phenotype Correlations in A Large Independent Cohort. Cancers. 2019;11:1838.

    Article  PubMed Central  CAS  Google Scholar 

  40. Ho IS, Hannan F, Guo HF, Hakker I, Zhong Y. Distinct functional domains of neurofibromatosis type 1 regulate immediate versus long-term memory formation. J Neurosci. 2007;27:6852–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Luo G, Kim J, Song K. The C-terminal domains of human neurofibromin and its budding yeast homologs Ira1 and Ira2 regulate the metaphase to anaphase transition. Cell Cycle. 2014;13:2780–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Li C, Cheng Y, Gutmann DA, Mangoura D. Differential localization of the neurofibromatosis 1 (NF1) gene product, neurofibromin, with the F-actin or microtubule cytoskeleton during differentiation of telencephalic neurons. Brain Res Dev Brain Res. 2001;130:231–48.

    Article  CAS  PubMed  Google Scholar 

  43. Vandenbroucke I, Van Oostveldt P, Coene E, et al. Neurofibromin is actively transported to the nucleus. FEBS Lett. 2004;560:98–102.

    Article  CAS  PubMed  Google Scholar 

  44. Patrakitkomjorn S, Kobayashi D, Morikawa T, Wilson MM, Tsubota N, Irie A, et al. Neurofibromatosis type 1 (NF1) tumor suppressor, neurofibromin, regulates the neuronal differentiation of PC12 cells via its associating protein, CRMP-2. J Biol Chem. 2008;283:9399–413.

    Article  CAS  PubMed  Google Scholar 

  45. Bellampalli SS, Khanna R. Towards a neurobiological understanding of pain in neurofibromatosis type 1: mechanisms and implications for treatment. Pain. 2019;160:1007–18.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Buono FD, Grau LE, Sprong ME, Morford KL, Johnson KJ, Gutmann DH. Pain symptomology, functional impact, and treatment of people with Neurofibromatosis type 1. J Pain Res. 2019;12:2555–61.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Afridi SK, Leschziner GD, Ferner RE. Prevalence and clinical presentation of headache in a National Neurofibromatosis 1 Service and impact on quality of life. Am J Med Genet A. 2015;167A:2282–5.

    Article  PubMed  Google Scholar 

  48. Wolters PL, Burns KM, Martin S, Baldwin A, Dombi E, Toledo-Tamula MA, et al. Pain interference in youth with neurofibromatosis type 1 and plexiform neurofibromas and relation to disease severity, social-emotional functioning, and quality of life. Am J Med Genet A. 2015;167A:2103–13.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Baralle FE, Giudice J. Alternative splicing as a regulator of development and tissue identity. Nat Rev Mol Cell Biol. 2017;18:437–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Assunto A, Ferrara U, De Luca A, Pivonello C, Lombardo L, Piscitelli A, et al. Isoform-specific NF1 mRNA levels correlate with disease severity in Neurofibromatosis type 1. Orphanet J Rare Dis. 2019;14:261.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Geist RT, Gutmann DH. Expression of a developmentally-regulated neuron-specific isoform of the neurofibromatosis 1 (NF1) gene. Neurosci Lett. 1996;211:85–8.

    Article  CAS  PubMed  Google Scholar 

  52. Marchuk DA, Saulino AM, Tavakkol R, Swaroop M, Wallace MR, Andersen LB, et al. cDNA cloning of the type 1 neurofibromatosis gene: complete sequence of the NF1 gene product. Genomics. 1991;11:931–40.

    Article  CAS  PubMed  Google Scholar 

  53. Kaufmann D, Muller R, Kenner O, Leistner W, Hein C, Vogel W, et al. The N-terminal splice product NF1-10a-2 of the NF1 gene codes for a transmembrane segment. Biochem Biophys Res Commun. 2002;294:496–503.

    Article  CAS  PubMed  Google Scholar 

  54. Costa RM, Yang T, Huynh DP, Pulst SM, Viskochil DH, Silva AJ, et al. Learning deficits, but normal development and tumor predisposition, in mice lacking exon 23a of Nf1. Nat Genet. 2001;27:399–405.

    Article  CAS  PubMed  Google Scholar 

  55. Fisher MJ, Belzberg AJ, de Blank P, De Raedt T, Elefteriou F, Ferner RE, et al. 2016 Children’s Tumor Foundation conference on neurofibromatosis type 1, neurofibromatosis type 2, and schwannomatosis. Am J Med Genet A. 2018;176:1258–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Andersen LB, Ballester R, Marchuk DA, Chang E, Gutmann DH, Saulino AM, et al. A conserved alternative splice in the von Recklinghausen neurofibromatosis (NF1) gene produces two neurofibromin isoforms, both of which have GTPase-activating protein activity. Mol Cell Biol. 1993;13:487–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Hinman MN, Sharma A, Luo G, Lou H. Neurofibromatosis type 1 alternative splicing is a key regulator of Ras signaling in neurons. Mol Cell Biol. 2014;34:2188–97.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Yunoue S, Tokuo H, Fukunaga K, Feng L, Ozawa T, Nishi T, et al. Neurofibromatosis type I tumor suppressor neurofibromin regulates neuronal differentiation via its GTPase-activating protein function toward Ras. J Biol Chem. 2003;278:26958–69.

    Article  CAS  PubMed  Google Scholar 

  59. Biayna J, Mazuelas H, Gel B, Terribas E, Dumbovic G, Rosas I, et al. Using antisense oligonucleotides for the physiological modulation of the alternative splicing of NF1 exon 23a during PC12 neuronal differentiation. Sci Rep. 2021;11:3661.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Vandenbroucke I, Vandesompele J, De Paepe A, Messiaen L. Quantification of NF1 transcripts reveals novel highly expressed splice variants. FEBS Lett. 2002;522:71–6.

    Article  CAS  PubMed  Google Scholar 

  61. Peta C, Tsirimonaki E, Samouil D, Georgiadou K, Mangoura D. Nuclear Isoforms of Neurofibromin Are Required for Proper Spindle Organization and Chromosome Segregation. Cells. 2020;9:2348.

    Article  PubMed Central  CAS  Google Scholar 

  62. Gutman DH, Andersen LB, Cole JL, Swaroop M, Collins FS. An alternatively-spliced mRNA in the carboxy terminus of the neurofibromatosis type 1 (NF1) gene is expressed in muscle. Hum Mol Genet. 1993;2:989–92.

    Article  CAS  PubMed  Google Scholar 

  63. Gutmann DH, Geist RT, Wright DE, Snider WD. Expression of the neurofibromatosis 1 (NF1) isoforms in developing and adult rat tissues. Cell Growth Differ. 1995;6:315–23.

    CAS  PubMed  Google Scholar 

  64. Summers MA, Quinlan KG, Payne JM, Little DG, North KN, Schindeler A. Skeletal muscle and motor deficits in Neurofibromatosis Type 1. J Musculoskelet Neuronal Interact. 2015;15:161–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Morris SW, Kirstein MN, Valentine MB, Dittmer KG, Shapiro DN, Saltman DL, et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Science. 1994;263:1281–4.

    Article  CAS  PubMed  Google Scholar 

  66. Della Corte CM, Viscardi G, Di Liello R, Fasano M, Martinelli E, Troiani T, et al. Role and targeting of anaplastic lymphoma kinase in cancer. Mol Cancer. 2018;17:30.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Gouzi JY, Moressis A, Walker JA, Apostolopoulou AA, Palmer RH, Bernards A, et al. The receptor tyrosine kinase Alk controls neurofibromin functions in Drosophila growth and learning. PLoS Genet. 2011;7:e1002281.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Walker JA, Bernards A. A Drosophila screen identifies neurofibromatosis-1 genetic modifiers involved in systemic and synaptic growth. Rare Dis. 2014;2:e28341.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Weiss JB, Weber S, Marzulla T, Raber J. Pharmacological inhibition of Anaplastic Lymphoma Kinase rescues spatial memory impairments in Neurofibromatosis 1 mutant mice. Behav Brain Res. 2017;332:337–42.

    Article  CAS  PubMed  Google Scholar 

  70. Brems H, Chmara M, Sahbatou M, Denayer E, Taniguchi K, Kato R, et al. Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype. Nat Genet. 2007;39:1120–6.

    Article  CAS  PubMed  Google Scholar 

  71. Pasmant E, Sabbagh A, Hanna N, Masliah-Planchon J, Jolly E, Goussard P, et al. SPRED1 germline mutations caused a neurofibromatosis type 1 overlapping phenotype. J Med Genet. 2009;46:425–30.

    Article  CAS  PubMed  Google Scholar 

  72. Yan W, Markegard E, Dharmaiah S, Urisman A, Drew M, Esposito D, et al. Structural Insights into the SPRED1-Neurofibromin-KRAS Complex and Disruption of SPRED1-Neurofibromin Interaction by Oncogenic EGFR. Cell Rep. 2020;32:107909.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Xie K, Colgan LA, Dao MT, Muntean BS, Sutton LP, Orlandi C, et al. NF1 Is a Direct G Protein Effector Essential for Opioid Signaling to Ras in the Striatum. Curr Biol. 2016;26:2992–3003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Roberts PJ, Der CJ. Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene. 2007;26:3291–310.

    Article  CAS  PubMed  Google Scholar 

  75. Wellbrock C, Karasarides M, Marais R. The RAF proteins take centre stage. Nat Rev Mol Cell Biol. 2004;5:875–85.

    Article  CAS  PubMed  Google Scholar 

  76. Chen Z, Liu C, Patel AJ, Liao CP, Wang Y, Le LQ. Cells of origin in the embryonic nerve roots for NF1-associated plexiform neurofibroma. Cancer Cell. 2014;26:695–706.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Gross AM, Wolters PL, Dombi E, Baldwin A, Whitcomb P, Fisher MJ, et al. Selumetinib in Children with Inoperable Plexiform Neurofibromas. N. Engl J Med. 2020;382:1430–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Ghadimi MP, Lopez G, Torres KE, Belousov R, Young ED, Liu J, et al. Targeting the PI3K/mTOR axis, alone and in combination with autophagy blockade, for the treatment of malignant peripheral nerve sheath tumors. Mol Cancer Ther. 2012;11:1758–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Johansson G, Mahller YY, Collins MH, Kim MO, Nobukuni T, Perentesis J, et al. Effective in vivo targeting of the mammalian target of rapamycin pathway in malignant peripheral nerve sheath tumors. Mol Cancer Ther. 2008;7:1237–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Weiss B, Widemann BC, Wolters P, Dombi E, Vinks A, Cantor A, et al. Sirolimus for progressive neurofibromatosis type 1-associated plexiform neurofibromas: a neurofibromatosis Clinical Trials Consortium phase II study. Neuro Oncol. 2015;17:596–603.

    Article  CAS  PubMed  Google Scholar 

  81. Weiss B, Widemann BC, Wolters P, Dombi E, Vinks AA, Cantor A, et al. Sirolimus for non-progressive NF1-associated plexiform neurofibromas: an NF clinical trials consortium phase II study. Pediatr Blood Cancer. 2014;61:982–6.

    Article  CAS  PubMed  Google Scholar 

  82. Widemann BC, Lu Y, Reinke D, Okuno SH, Meyer CF, Cote GM, et al. Targeting Sporadic and Neurofibromatosis Type 1 (NF1) Related Refractory Malignant Peripheral Nerve Sheath Tumors (MPNST) in a Phase II Study of Everolimus in Combination with Bevacizumab (SARC016). Sarcoma. 2019;2019:7656747.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Krebs EG, Fischer EH. The phosphorylase b to a converting enzyme of rabbit skeletal muscle. Biochim Biophys Acta. 1956;20:150–7.

    Article  CAS  PubMed  Google Scholar 

  84. Guo HF, The I, Hannan F, Bernards A, Zhong Y. Requirement of Drosophila NF1 for activation of adenylyl cyclase by PACAP38-like neuropeptides. Science. 1997;276:795–8.

    Article  CAS  PubMed  Google Scholar 

  85. Guo HF, Tong J, Hannan F, Luo L, Zhong Y. A neurofibromatosis-1-regulated pathway is required for learning in Drosophila. Nature. 2000;403:895–8.

    Article  CAS  PubMed  Google Scholar 

  86. The I, Hannigan GE, Cowley GS, Reginald S, Zhong Y, Gusella JF, et al. Rescue of a Drosophila NF1 mutant phenotype by protein kinase A. Science. 1997;276:791–4.

    Article  CAS  PubMed  Google Scholar 

  87. Wolman MA, de Groh ED, McBride SM, Jongens TA, Granato M, Epstein JA. Modulation of cAMP and ras signaling pathways improves distinct behavioral deficits in a zebrafish model of neurofibromatosis type 1. Cell Rep. 2014;8:1265–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Brown JA, Gianino SM, Gutmann DH. Defective cAMP generation underlies the sensitivity of CNS neurons to neurofibromatosis-1 heterozygosity. J Neurosci. 2010;30:5579–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Tong J, Hannan F, Zhu Y, Bernards A, Zhong Y. Neurofibromin regulates G protein-stimulated adenylyl cyclase activity. Nat Neurosci. 2002;5:95–6.

    Article  CAS  PubMed  Google Scholar 

  90. Warrington NM, Gianino SM, Jackson E, Goldhoff P, Garbow JR, Piwnica-Worms D, et al. Cyclic AMP suppression is sufficient to induce gliomagenesis in a mouse model of neurofibromatosis-1. Cancer Res. 2010;70:5717–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Kim HA, Ratner N, Roberts TM, Stiles CD. Schwann cell proliferative responses to cAMP and Nf1 are mediated by cyclin D1. J Neurosci. 2001;21:1110–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Dang I, De Vries GH. Aberrant cAMP metabolism in NF1 malignant peripheral nerve sheath tumor cells. Neurochem Res. 2011;36:1697–705.

    Article  CAS  PubMed  Google Scholar 

  93. Volta M, Calza S, Roberts AM, Roberts RG. Characterisation of the interaction between syndecan-2, neurofibromin and CASK: dependence of interaction on syndecan dimerization. Biochem Biophys Res Commun. 2010;391:1216–21.

    Article  CAS  PubMed  Google Scholar 

  94. Lin YL, Lei YT, Hong CJ, Hsueh YP. Syndecan-2 induces filopodia and dendritic spine formation via the neurofibromin-PKA-Ena/VASP pathway. J Cell Biol. 2007;177:829–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Williams TM, Lisanti MP. The caveolin proteins. Genome Biol. 2004;5:214.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Yang K, Du J, Shi D, Ji F, Ji Y, Pan J, et al. Knockdown of MSI2 inhibits metastasis by interacting with caveolin-1 and inhibiting its ubiquitylation in human NF1-MPNST cells. Cell Death Dis. 2020;11:489.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Chen Z, Mo J, Brosseau JP, Shipman T, Wang Y, Liao CP, et al. Spatiotemporal Loss of NF1 in Schwann Cell Lineage Leads to Different Types of Cutaneous Neurofibroma Susceptible to Modification by the Hippo Pathway. Cancer Disco. 2019;9:114–29.

    Article  CAS  Google Scholar 

  98. Faden DL, Asthana S, Tihan T, DeRisi J, Kliot M. Whole Exome Sequencing of Growing and Non-Growing Cutaneous Neurofibromas from a Single Patient with Neurofibromatosis Type 1. PLoS One. 2017;12:e0170348.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Wu LMN, Deng Y, Wang J, Zhao C, Wang J, Rao R, et al. Programming of Schwann Cells by Lats1/2-TAZ/YAP Signaling Drives Malignant Peripheral Nerve Sheath Tumorigenesis. Cancer Cell. 2018;33:292–308 e297.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Yang J, Ylipaa A, Sun Y, Zheng H, Chen K, Nykter M, et al. Genomic and molecular characterization of malignant peripheral nerve sheath tumor identifies the IGF1R pathway as a primary target for treatment. Clin Cancer Res. 2011;17:7563–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Prunier C, Prudent R, Kapur R, Sadoul K, Lafanechere L. LIM kinases: cofilin and beyond. Oncotarget. 2017;8:41749–63.

    Article  PubMed  PubMed Central  Google Scholar 

  102. Ozawa T, Araki N, Yunoue S, Tokuo H, Feng L, Patrakitkomjorn S, et al. The neurofibromatosis type 1 gene product neurofibromin enhances cell motility by regulating actin filament dynamics via the Rho-ROCK-LIMK2-cofilin pathway. J Biol Chem. 2005;280:39524–33.

    Article  CAS  PubMed  Google Scholar 

  103. Amano M, Tsumura Y, Taki K, Harada H, Mori K, Nishioka T, et al. A proteomic approach for comprehensively screening substrates of protein kinases such as Rho-kinase. PLoS One. 2010;5:e8704.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Yu H, Lee H, Herrmann A, Buettner R, Jove R. Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nat Rev Cancer. 2014;14:736–46.

    Article  CAS  PubMed  Google Scholar 

  105. Wu J, Keng VW, Patmore DM, Kendall JJ, Patel AV, Jousma E, et al. Insertional Mutagenesis Identifies a STAT3/Arid1b/beta-catenin Pathway Driving Neurofibroma Initiation. Cell Rep. 2016;14:1979–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Qureshy Z, Johnson DE, Grandis JR, et al. Targeting the JAK/STAT pathway in solid tumors. J Cancer Metastasis Treat. 2020;6:27.

    PubMed  PubMed Central  Google Scholar 

  107. Rischin A, De T, Silva, Le Marshall K. Reversible eruption of neurofibromatosis associated with tofacitinib therapy for rheumatoid arthritis. Rheumatol (Oxf). 2019;58:1111–3.

    Article  Google Scholar 

  108. Cancer Genome Atlas, N. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490:61–70.

    Article  CAS  Google Scholar 

  109. Bertucci F, Ng CKY, Patsouris A, Droin N, Piscuoglio S, Carbuccia N, et al. Genomic characterization of metastatic breast cancers. Nature. 2019;569:560–4.

    Article  CAS  PubMed  Google Scholar 

  110. Yates LR, Knappskog S, Wedge D, Farmery JHR, Gonzalez S, Martincorena I, et al. Genomic evolution of breast cancer metastasis and relapse. Cancer Cell. 2017;32:169–184. e167.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Zheng ZY, Anurag M, Lei JT, Cao J, Singh P, Peng J, et al. Neurofibromin is an estrogen receptor-alpha transcriptional co-repressor in breast cancer. Cancer Cell. 2020;37:387–402. e387.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Brosseau JP, Liao CP, Le LQ. Translating current basic research into future therapies for neurofibromatosis type 1. Br J Cancer. 2020;123:178–86.

    Article  PubMed  PubMed Central  Google Scholar 

  113. Rao UN, Sonmez-Alpan E, Michalopoulos GK. Hepatocyte growth factor and c-MET in benign and malignant peripheral nerve sheath tumors. Hum Pathol. 1997;28:1066–70.

    Article  CAS  PubMed  Google Scholar 

  114. Wang J, Pollard K, Calizo A, Pratilas CA. Activation of Receptor Tyrosine Kinases Mediates Acquired Resistance to MEK Inhibition in Malignant Peripheral Nerve Sheath Tumors. Cancer Res. 2021;81:747–62.

    Article  CAS  PubMed  Google Scholar 

  115. Trauger JW, Baird EE, Dervan PB. Recognition of DNA by designed ligands at subnanomolar concentrations. Nature. 1996;382:559–61.

    Article  CAS  PubMed  Google Scholar 

  116. Brannan CI, Perkins AS, Vogel KS, Ratner N, Nordlund ML, Reid SW, et al. Targeted disruption of the neurofibromatosis type-1 gene leads to developmental abnormalities in heart and various neural crest-derived tissues. Genes Dev. 1994;8:1019–29.

    Article  CAS  PubMed  Google Scholar 

  117. Jacks T, Shih TS, Schmitt EM, Bronson RT, Bernards A, Weinberg RA. Tumour predisposition in mice heterozygous for a targeted mutation in Nf1. Nat Genet. 1994;7:353–61.

    Article  CAS  PubMed  Google Scholar 

  118. Zhu Y, Romero MI, Ghosh P, Ye Z, Charnay P, Rushing EJ, et al. Ablation of NF1 function in neurons induces abnormal development of cerebral cortex and reactive gliosis in the brain. Genes Dev. 2001;15:859–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Bajenaru ML, Zhu Y, Hedrick NM, Donahoe J, Parada LF, Gutmann DH. Astrocyte-specific inactivation of the neurofibromatosis 1 gene (NF1) is insufficient for astrocytoma formation. Mol Cell Biol. 2002;22:5100–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Wang W, Nyman JS, Ono K, Stevenson DA, Yang X, Elefteriou F. Mice lacking Nf1 in osteochondroprogenitor cells display skeletal dysplasia similar to patients with neurofibromatosis type I. Hum Mol Genet. 2011;20:3910–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Zhu Y, Harada T, Liu L, Lush ME, Guignard F, Harada C, et al. Inactivation of NF1 in CNS causes increased glial progenitor proliferation and optic glioma formation. Development. 2005;132:5577–88.

    Article  CAS  PubMed  Google Scholar 

  122. Dasgupta B, Gutmann DH. Neurofibromin regulates neural stem cell proliferation, survival, and astroglial differentiation in vitro and in vivo. J Neurosci. 2005;25:5584–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Jecrois, ES, Zheng W, Bornhorst M, Li Y, Treisman DM, Muguyo D, et al. Treatment during a developmental window prevents NF1-associated optic pathway gliomas by targeting Erk-dependent migrating glial progenitors. Dev Cell. 2021;56:2871–85.

  124. Mo J, Anastasaki C, Chen Z, Shipman T, Papke J, Yin K, et al. Humanized neurofibroma model from induced pluripotent stem cells delineates tumor pathogenesis and developmental origins. J Clin Investig. 2021;131:e139807.

    Article  PubMed Central  Google Scholar 

  125. Pemov A, Park C, Reilly KM, Stewart DR. Evidence of perturbations of cell cycle and DNA repair pathways as a consequence of human and murine NF1-haploinsufficiency. BMC Genomics. 2010;11:194.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. Koliou X, Fedonidis C, Kalpachidou T, Mangoura D. Nuclear import mechanism of neurofibromin for localization on the spindle and function in chromosome congression. J Neurochem. 2016;136:78–91.

    Article  CAS  PubMed  Google Scholar 

  127. Hiatt K, Ingram DA, Huddleston H, Spandau DF, Kapur R, Clapp DW. Loss of the nf1 tumor suppressor gene decreases fas antigen expression in myeloid cells. Am J Pathol. 2004;164:1471–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Shapira S, Barkan B, Friedman E, Kloog Y, Stein R. The tumor suppressor neurofibromin confers sensitivity to apoptosis by Ras-dependent and Ras-independent pathways. Cell Death Differ. 2007;14:895–906.

    Article  CAS  PubMed  Google Scholar 

  129. Yang FC, Ingram DA, Chen S, Hingtgen CM, Ratner N, Monk KR, et al. Neurofibromin-deficient Schwann cells secrete a potent migratory stimulus for Nf1+/- mast cells. J Clin Invest. 2003;112:1851–61.

    Article  CAS  PubMed  Google Scholar 

  130. Liao CP, Booker RC, Brosseau JP, Chen Z, Mo J, Tchegnon E, et al. Contributions of inflammation and tumor microenvironment to neurofibroma tumorigenesis. J Clin Investig. 2018;128:2848–61.

    Article  PubMed  PubMed Central  Google Scholar 

  131. Yang FC, Chen S, Clegg T, Li X, Morgan T, Estwick SA, et al. Nf1+/- mast cells induce neurofibroma like phenotypes through secreted TGF-beta signaling. Hum Mol Genet. 2006;15:2421–37.

    Article  CAS  PubMed  Google Scholar 

  132. Choi K, Komurov K, Fletcher JS, Jousma E, Cancelas JA, Wu J, et al. An inflammatory gene signature distinguishes neurofibroma Schwann cells and macrophages from cells in the normal peripheral nervous system. Sci Rep. 2017;7:43315.

    Article  PubMed  PubMed Central  Google Scholar 

  133. Aras S, Zaidi MR. TAMeless traitors: macrophages in cancer progression and metastasis. Br J Cancer. 2017;117:1583–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Mantovani A, Allavena P. The interaction of anticancer therapies with tumor-associated macrophages. J Exp Med. 2015;212:435–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Ries CH, Cannarile MA, Hoves S, Benz J, Wartha K, Runza V, et al. Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy. Cancer Cell. 2014;25:846–59.

    Article  CAS  PubMed  Google Scholar 

  136. Patwardhan PP, Surriga O, Beckman MJ, de Stanchina E, Dematteo RP, Tap WD, et al. Sustained inhibition of receptor tyrosine kinases and macrophage depletion by PLX3397 and rapamycin as a potential new approach for the treatment of MPNSTs. Clin Cancer Res. 2014;20:3146–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Fletcher JS, Wu J, Jessen WJ, Pundavela J, Miller JA, Dombi E, et al. Cxcr3-expressing leukocytes are necessary for neurofibroma formation in mice. JCI Insight. 2019;4:e98601.

    Article  PubMed Central  Google Scholar 

  138. Farschtschi S, Park SJ, Sawitzki B, Oh SJ, Kluwe L, Mautner VF, et al. Effector T cell subclasses associate with tumor burden in neurofibromatosis type 1 patients. Cancer Immunol Immunother. 2016;65:1113–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Brosseau JP, Liao CP, Wang Y, Ramani V, Vandergriff T, Lee M, et al. NF1 heterozygosity fosters de novo tumorigenesis but impairs malignant transformation. Nat Commun. 2018;9:5014.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  140. Liu J, Gallo RM, Khan MA, Renukaradhya GJ, Brutkiewicz RR. Neurofibromin 1 Impairs Natural Killer T-Cell-Dependent Antitumor Immunity against a T-Cell Lymphoma. Front Immunol. 2017;8:1901.

    Article  PubMed  CAS  Google Scholar 

  141. Knudson AG Jr. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA. 1971;68:820–3.

    Article  PubMed  PubMed Central  Google Scholar 

  142. Walker JA, Upadhyaya M. Emerging therapeutic targets for neurofibromatosis type 1. Expert Opin Ther Targets. 2018;22:419–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Kluwe L, Friedrich R, Mautner VF. Loss of NF1 allele in Schwann cells but not in fibroblasts derived from an NF1-associated neurofibroma. Genes Chromosomes Cancer. 1999;24:283–5.

    Article  CAS  PubMed  Google Scholar 

  144. Legius E, Marchuk DA, Collins FS, Glover TW. Somatic deletion of the neurofibromatosis type 1 gene in a neurofibrosarcoma supports a tumour suppressor gene hypothesis. Nat Genet. 1993;3:122–6.

    Article  CAS  PubMed  Google Scholar 

  145. Steinmann K, Kluwe L, Friedrich RE, Mautner VF, Cooper DN, Kehrer-Sawatzki H. Mechanisms of loss of heterozygosity in neurofibromatosis type 1-associated plexiform neurofibromas. J Investig Dermatol. 2009;129:615–21.

    Article  CAS  PubMed  Google Scholar 

  146. Daginakatte GC, Gutmann DH. Neurofibromatosis-1 (Nf1) heterozygous brain microglia elaborate paracrine factors that promote Nf1-deficient astrocyte and glioma growth. Hum Mol Genet. 2007;16:1098–112.

    Article  CAS  PubMed  Google Scholar 

  147. De Schepper S, Maertens O, Callens T, Naeyaert JM, Lambert J, Messiaen L. Somatic mutation analysis in NF1 cafe au lait spots reveals two NF1 hits in the melanocytes. J Investig Dermatol. 2008;128:1050–3.

    Article  PubMed  CAS  Google Scholar 

  148. Paria N, Cho TJ, Choi IH, Kamiya N, Kayembe K, Mao R, et al. Neurofibromin deficiency-associated transcriptional dysregulation suggests a novel therapy for tibial pseudoarthrosis in NF1. J Bone Min Res. 2014;29:2636–42.

    Article  CAS  Google Scholar 

  149. Le LQ, Liu C, Shipman T, Chen Z, Suter U, Parada LF. Susceptible stages in Schwann cells for NF1-associated plexiform neurofibroma development. Cancer Res. 2011;71:4686–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Wu J, Williams JP, Rizvi TA, Kordich JJ, Witte D, Meijer D, et al. Plexiform and dermal neurofibromas and pigmentation are caused by Nf1 loss in desert hedgehog-expressing cells. Cancer Cell. 2008;13:105–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Dombi E, Baldwin A, Marcus LJ, Fisher MJ, Weiss B, Kim A, et al. Activity of Selumetinib in Neurofibromatosis Type 1-Related Plexiform Neurofibromas. N. Engl J Med. 2016;375:2550–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2005;2:e73.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  153. Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science. 2001;293:876–80.

    Article  CAS  PubMed  Google Scholar 

  154. Lito P, Rosen N, Solit DB. Tumor adaptation and resistance to RAF inhibitors. Nat Med. 2013;19:1401–9.

    Article  CAS  PubMed  Google Scholar 

  155. Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011;3:75ra26.

    Article  PubMed  PubMed Central  Google Scholar 

  156. Beltran H, Rickman DS, Park K, Chae SS, Sboner A, MacDonald TY, et al. Molecular characterization of neuroendocrine prostate cancer and identification of new drug targets. Cancer Discov. 2011;1:487–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Bailleul B, Surani MA, White S, Barton SC, Brown K, Blessing M, et al. Skin hyperkeratosis and papilloma formation in transgenic mice expressing a ras oncogene from a suprabasal keratin promoter. Cell. 1990;62:697–708.

    Article  CAS  PubMed  Google Scholar 

  158. Brown K, Strathdee D, Bryson S, Lambie W, Balmain A. The malignant capacity of skin tumours induced by expression of a mutant H-ras transgene depends on the cell type targeted. Curr Biol. 1998;8:516–24.

    Article  CAS  PubMed  Google Scholar 

  159. Scadden DT. Nice neighborhood: emerging concepts of the stem cell niche. Cell. 2014;157:41–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Korkaya H, Liu S, Wicha MS. Breast cancer stem cells, cytokine networks, and the tumor microenvironment. J Clin Investig. 2011;121:3804–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Bayik D, Lathia JD. Cancer stem cell-immune cell crosstalk in tumour progression. Nat Rev Cancer. 2021;21:526–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Chen, Y, McAndrews KM, Kalluri R. Clinical and therapeutic relevance of cancer-associated fibroblasts. Nat Rev Clin Oncol. 2021.

  163. Jones DL, Wagers AJ. No place like home: anatomy and function of the stem cell niche. Nat Rev Mol Cell Biol. 2008;9:11–21.

    Article  CAS  PubMed  Google Scholar 

  164. Sell S. On the stem cell origin of cancer. Am J Pathol. 2010;176:2584–494.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Smith BA, Sokolov A, Uzunangelov V, Baertsch R, Newton Y, Graim K, et al. A basal stem cell signature identifies aggressive prostate cancer phenotypes. Proc Natl Acad Sci USA. 2015;112:E6544–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Chaffer CL, Brueckmann I, Scheel C, Kaestli AJ, Wiggins PA, Rodrigues LO, et al. Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state. Proc Natl Acad Sci USA. 2011;108:7950–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Marjanovic ND, Weinberg RA, Chaffer CL. Cell plasticity and heterogeneity in cancer. Clin Chem. 2013;59:168–79.

    Article  CAS  PubMed  Google Scholar 

  168. Friedmann-Morvinski D, Verma IM. Dedifferentiation and reprogramming: origins of cancer stem cells. EMBO Rep. 2014;15:244–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Feinberg AP, Ohlsson R, Henikoff S. The epigenetic progenitor origin of human cancer. Nat Rev Genet. 2006;7:21–33.

    Article  CAS  PubMed  Google Scholar 

  170. Shukla V, Vaissiere T, Herceg Z. Histone acetylation and chromatin signature in stem cell identity and cancer. Mutat Res. 2008;637:1–15.

    Article  CAS  PubMed  Google Scholar 

  171. Delpu Y, Cordelier P, Cho WC, Torrisani J. DNA methylation and cancer diagnosis. Int J Mol Sci. 2013;14:15029–58.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  172. Berdasco M, Esteller M. Aberrant epigenetic landscape in cancer: how cellular identity goes awry. Dev Cell. 2010;19:698–711.

    Article  CAS  PubMed  Google Scholar 

  173. Baylin SB, Jones PA. A decade of exploring the cancer epigenome - biological and translational implications. Nat Rev Cancer. 2011;11:726–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Ohm JE, McGarvey KM, Yu X, Cheng L, Schuebel KE, Cope L, et al. A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing. Nat Genet. 2007;39:237–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Jones PA, Baylin SB. The epigenomics of cancer. Cell. 2007;128:683–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Arthur LL, Chung JJ, Jankirama P, Keefer KM, Kolotilin I, Pavlovic-Djuranovic S, et al. Rapid generation of hypomorphic mutations. Nat Commun. 2017;8:14112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Pinna V, Lanari V, Daniele P, Consoli F, Agolini E, Margiotti K, et al. p.Arg1809Cys substitution in neurofibromin is associated with a distinctive NF1 phenotype without neurofibromas. Eur J Hum Genet. 2015;23:1068–71.

    Article  CAS  PubMed  Google Scholar 

  178. Upadhyaya M, Huson SM, Davies M, Thomas N, Chuzhanova N, Giovannini S, et al. An absence of cutaneous neurofibromas associated with a 3-bp inframe deletion in exon 17 of the NF1 gene (c.2970-2972 delAAT): evidence of a clinically significant NF1 genotype-phenotype correlation. Am J Hum Genet. 2007;80:140–51.

    Article  CAS  PubMed  Google Scholar 

  179. Murthy V, Tebaldi T, Yoshida T, Erdin S, Calzonetti T, Vijayvargia R, et al. Hypomorphic mutation of the mouse Huntington’s disease gene orthologue. PLoS Genet. 2019;15:e1007765.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Anastasaki C, Woo AS, Messiaen LM, Gutmann DH. Elucidating the impact of neurofibromatosis-1 germline mutations on neurofibromin function and dopamine-based learning. Hum Mol Genet. 2015;24:3518–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Philpott C, Tovell H, Frayling IM, Cooper DN, Upadhyaya M. The NF1 somatic mutational landscape in sporadic human cancers. Hum Genomics. 2017;11:13.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  182. Tabata MM, Li S, Knight P, Bakker A, Sarin KY. Phenotypic heterogeneity of neurofibromatosis type 1 in a large international registry. JCI Insight. 2020;5:e136262.

    Article  PubMed Central  Google Scholar 

  183. Koczkowska M, Callens T, Chen Y, Gomes A, Hicks AD, Sharp A, et al. Clinical spectrum of individuals with pathogenic NF1 missense variants affecting p.Met1149, p.Arg1276, and p.Lys1423: genotype-phenotype study in neurofibromatosis type 1. Hum Mutat. 2020;41:299–315.

    Article  CAS  PubMed  Google Scholar 

  184. Kehrer-Sawatzki H, Mautner VF, Cooper DN. Emerging genotype-phenotype relationships in patients with large NF1 deletions. Hum Genet. 2017;136:349–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Serra G, Antona V, Corsello G, Zara F, Piro E, Falsaperla R. NF1 microdeletion syndrome: case report of two new patients. Ital J Pediatr. 2019;45:138.

    Article  PubMed  PubMed Central  Google Scholar 

  186. Pacot L, Vidaud D, Sabbagh A, Laurendeau I, Briand-Suleau A, Coustier A, et al. Severe phenotype in patients with large deletions of NF1. Cancers. 2021;13:2963.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  187. Wegscheid ML, Anastasaki C, Hartigan KA, Cobb OM, Papke JB, Traber JN, et al. Patient-derived iPSC-cerebral organoid modeling of the 17q11.2 microdeletion syndrome establishes CRLF3 as a critical regulator of neurogenesis. Cell Rep. 2021;36:109315.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Anastasaki C, Morris SM, Gao F, Gutmann DH. Children with 5’-end NF1 gene mutations are more likely to have glioma. Neurol Genet. 2017;3:e192.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Anastasaki C, Gao F, Gutmann DH. Commentary: Identification of Mutation Regions on NF1 Responsible for High- and Low-Risk Development of Optic Pathway Glioma in Neurofibromatosis Type I. Front Genet. 2019;10:115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Bolcekova A, Nemethova M, Zatkova A, Hlinkova K, Pozgayova S, Hlavata A, et al. Clustering of mutations in the 5’ tertile of the NF1 gene in Slovakia patients with optic pathway glioma. Neoplasma. 2013;60:655–65.

    Article  CAS  PubMed  Google Scholar 

  191. Sharif S, Upadhyaya M, Ferner R, Majounie E, Shenton A, Baser M, et al. A molecular analysis of individuals with neurofibromatosis type 1 (NF1) and optic pathway gliomas (OPGs), and an assessment of genotype-phenotype correlations. J Med Genet. 2011;48:256–60.

    Article  CAS  PubMed  Google Scholar 

  192. Hutter S, Piro RM, Waszak SM, Kehrer-Sawatzki H, Friedrich RE, Lassaletta A, et al. No correlation between NF1 mutation position and risk of optic pathway glioma in 77 unrelated NF1 patients. Hum Genet. 2016;135:469–75.

    Article  CAS  PubMed  Google Scholar 

  193. Koczkowska M, Chen Y, Callens T, Gomes A, Sharp A, Johnson S, et al. Genotype-Phenotype Correlation in NF1: Evidence for a More Severe Phenotype Associated with Missense Mutations Affecting NF1 Codons 844-8. Am J Hum Genet. 2018;102:69–87.

    Article  CAS  PubMed  Google Scholar 

  194. Scala, M, I Schiavetti, F Madia, C Chelleri, G Piccolo, A Accogli, et al., Genotype-Phenotype Correlations in Neurofibromatosis Type 1: A Single-Center Cohort Study. Cancers 2021;13:1879.

  195. Rojnueangnit K, Xie J, Gomes A, Sharp A, Callens T, Chen Y, et al. High Incidence of Noonan Syndrome Features Including Short Stature and Pulmonic Stenosis in Patients carrying NF1 Missense Mutations Affecting p.Arg1809: Genotype-Phenotype Correlation. Hum Mutat. 2015;36:1052–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Santoro C, Maietta A, Giugliano T, Melis D, Perrotta S, Nigro V, et al. Arg(1809) substitution in neurofibromin: further evidence of a genotype-phenotype correlation in neurofibromatosis type 1. Eur J Hum Genet. 2015;23:1460–1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Anastasaki C, Wegscheid ML, Hartigan K, Papke JB, Kopp ND, Chen J, et al. Human iPSC-Derived Neurons and Cerebral Organoids Establish Differential Effects of Germline NF1 Gene Mutations. Stem Cell Rep. 2020;14:541–50.

    Article  CAS  Google Scholar 

  198. Koczkowska M, Callens T, Gomes A, Sharp A, Chen Y, Hicks AD, et al. Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype-phenotype correlation. Genet Med. 2019;21:867–76.

    Article  CAS  PubMed  Google Scholar 

  199. Artandi SE, Chang S, Lee SL, Alson S, Gottlieb GJ, Chin L, et al. Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice. Nature. 2000;406:641–5.

    Article  CAS  PubMed  Google Scholar 

  200. Jones RE, Grimstead JW, Sedani A, Baird D, Upadhyaya M. Telomere erosion in NF1 tumorigenesis. Oncotarget. 2017;8:40132–9.

    Article  PubMed  PubMed Central  Google Scholar 

  201. Rodriguez FJ, Graham MK, Brosnan-Cashman JA, Barber JR, Davis C, Vizcaino MA, et al. Telomere alterations in neurofibromatosis type 1-associated solid tumors. Acta Neuropathol Commun. 2019;7:139.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  202. Subramanian S, Thayanithy V, West RB, Lee CH, Beck AH, Zhu S, et al. Genome-wide transcriptome analyses reveal p53 inactivation mediated loss of miR-34a expression in malignant peripheral nerve sheath tumours. J Pathol. 2010;220:58–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Presneau N, Eskandarpour M, Shemais T, Henderson S, Halai D, Tirabosco R, et al. MicroRNA profiling of peripheral nerve sheath tumours identifies miR-29c as a tumour suppressor gene involved in tumour progression. Br J Cancer. 2013;108:964–72.

    Article  CAS  PubMed  Google Scholar 

  204. Gong M, Ma J, Li M, Zhou M, Hock JM, Yu X. MicroRNA-204 critically regulates carcinogenesis in malignant peripheral nerve sheath tumors. Neuro Oncol. 2012;14:1007–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Amirnasr A, Verdijk RM, van Kuijk PF, Kartal P, Vriends ALM, French PJ, et al. Deregulated microRNAs in neurofibromatosis type 1 derived malignant peripheral nerve sheath tumors. Sci Rep. 2020;10:2927.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Chai G, Liu N, Ma J, Li H, Oblinger JL, Prahalad AK, et al. MicroRNA-10b regulates tumorigenesis in neurofibromatosis type 1. Cancer Sci. 2010;101:1997–2004.

    Article  CAS  PubMed  Google Scholar 

  207. Itani S, Kunisada T, Morimoto Y, Yoshida A, Sasaki T, Ito S, et al. MicroRNA-21 correlates with tumorigenesis in malignant peripheral nerve sheath tumor (MPNST) via programmed cell death protein 4 (PDCD4). J Cancer Res Clin Oncol. 2012;138:1501–9.

    Article  CAS  PubMed  Google Scholar 

  208. Cancer Genome Atlas, N. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487:330–7.

    Article  CAS  Google Scholar 

  209. Cancer Genome Atlas Research, N. Comprehensive genomic characterization of squamous cell lung cancers. Nature. 2012;489:519–25.

    Article  CAS  Google Scholar 

  210. Cancer Genome Atlas Research, N. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. 2014;507:315–22.

    Article  CAS  Google Scholar 

  211. Holzel M, Huang S, Koster J, Ora I, Lakeman A, Caron H, et al. NF1 is a tumor suppressor in neuroblastoma that determines retinoic acid response and disease outcome. Cell. 2010;142:218–29.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  212. Kalender Atak Z, De Keersmaecker K, Gianfelici V, Geerdens E, Vandepoel R, Pauwels D, et al. High accuracy mutation detection in leukemia on a selected panel of cancer genes. PLoS One. 2012;7:e38463.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  213. Sjoblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD, et al. The consensus coding sequences of human breast and colorectal cancers. Science. 2006;314:268–74.

    Article  PubMed  CAS  Google Scholar 

  214. Stephens PJ, Tarpey PS, Davies H, Van Loo P, Greenman C, Wedge DC, et al. The landscape of cancer genes and mutational processes in breast cancer. Nature. 2012;486:400–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD, Cibulskis K, et al. Somatic mutations affect key pathways in lung adenocarcinoma. Nature. 2008;455:1069–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Imielinski M, Berger AH, Hammerman PS, Hernandez B, Pugh TJ, Hodis E, et al. Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell. 2012;150:1107–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Kan Z, Jaiswal BS, Stinson J, Janakiraman V, Bhatt D, Stern HM, et al. Diverse somatic mutation patterns and pathway alterations in human cancers. Nature. 2010;466:869–73.

    Article  CAS  PubMed  Google Scholar 

  218. Cooke SL, Ng CK, Melnyk N, Garcia MJ, Hardcastle T, Temple J, et al. Genomic analysis of genetic heterogeneity and evolution in high-grade serous ovarian carcinoma. Oncogene. 2010;29:4905–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Gorringe, KL, George J, Anglesio MS, Ramakrishna M, Etemadmoghadam D, Cowin P, et al. Copy number analysis identifies novel interactions between genomic loci in ovarian cancer. PLoS One. 2010;5:e11408.

  220. Sangha N, Wu R, Kuick R, Powers S, Mu D, Fiander D, et al. Neurofibromin 1 (NF1) defects are common in human ovarian serous carcinomas and co-occur with TP53 mutations. Neoplasia. 2008;10:1362–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Shain AH, Yeh I, Kovalyshyn I, Sriharan A, Talevich E, Gagnon A, et al. The Genetic Evolution of Melanoma from Precursor Lesions. N. Engl J Med. 2015;373:1926–36.

    Article  PubMed  CAS  Google Scholar 

  222. Wiesner T, Kiuru M, Scott SN, Arcila M, Halpern AC, Hollmann T, et al. NF1 Mutations Are Common in Desmoplastic Melanoma. Am J Surg Pathol. 2015;39:1357–62.

    Article  PubMed  PubMed Central  Google Scholar 

  223. Whittaker SR, Theurillat JP, Van Allen E, Wagle N, Hsiao J, Cowley GS, et al. A genome-scale RNA interference screen implicates NF1 loss in resistance to RAF inhibition. Cancer Disco. 2013;3:350–62.

    Article  CAS  Google Scholar 

  224. de Bruin EC, Cowell C, Warne PH, Jiang M, Saunders RE, Melnick MA, et al. Reduced NF1 expression confers resistance to EGFR inhibition in lung cancer. Cancer Disco. 2014;4:606–19.

    Article  CAS  Google Scholar 

  225. Pearson A, Proszek P, Pascual J, Fribbens C, Shamsher MK, Kingston B, et al. Inactivating NF1 Mutations Are Enriched in Advanced Breast Cancer and Contribute to Endocrine Therapy Resistance. Clin Cancer Res. 2020;26:608–22.

    Article  CAS  PubMed  Google Scholar 

  226. Russell S, Bennett J, Wellman JA, Chung DC, Yu ZF, Tillman A, et al. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet. 2017;390:849–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Cehajic-Kapetanovic J, Xue K, Martinez-Fernandez de la Camara C, Nanda A, Davies A, Wood LJ, et al. Initial results from a first-in-human gene therapy trial on X-linked retinitis pigmentosa caused by mutations in RPGR. Nat Med. 2020;26:354–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Mamcarz E, Zhou S, Lockey T, Abdelsamed H, Cross SJ, Kang G, et al. Lentiviral Gene Therapy Combined with Low-Dose Busulfan in Infants with SCID-X1. N. Engl J Med. 2019;380:1525–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Perrin GQ, Herzog RW, Markusic DM. Update on clinical gene therapy for hemophilia. Blood. 2019;133:407–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Bodempudi V, Yamoutpoor F, Pan W, Dudek AZ, Esfandyari T, Piedra M, et al. Ral overactivation in malignant peripheral nerve sheath tumors. Mol Cell Biol. 2009;29:3964–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. Thomas SL, Deadwyler GD, Tang J, Stubbs EB Jr., Muir D, Hiatt KK, et al. Reconstitution of the NF1 GAP-related domain in NF1-deficient human Schwann cells. Biochem Biophys Res Commun. 2006;348:971–80.

    Article  CAS  PubMed  Google Scholar 

  232. Bai RY, Esposito D, Tam AJ, McCormick F, Riggins GJ, Wade Clapp D, et al. Feasibility of using NF1-GRD and AAV for gene replacement therapy in NF1-associated tumors. Gene Ther. 2019;26:277–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Cui Y, Morrison H. Construction of cloning-friendly minigenes for mammalian expression of full-length human NF1 isoforms. Hum Mutat. 2019;40:187–92.

    Article  CAS  PubMed  Google Scholar 

  234. Ismat FA, Xu J, Lu MM, Epstein JA. The neurofibromin GAP-related domain rescues endothelial but not neural crest development in Nf1 mice. J Clin Investig. 2006;116:2378–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  235. Eyquem J, Mansilla-Soto J, Giavridis T, van der Stegen SJ, Hamieh M, Cunanan KM, et al. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature. 2017;543:113–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Dunbar, CE, KA High, JK Joung, DB Kohn, K Ozawa, and M Sadelain, Gene therapy comes of age. Science. 2018;359:eaan4672.

  237. Wei T, Cheng Q, Min YL, Olson EN, Siegwart DJ. Systemic nanoparticle delivery of CRISPR-Cas9 ribonucleoproteins for effective tissue specific genome editing. Nat Commun. 2020;11:3232.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Lee K, Conboy M, Park HM, Jiang F, Kim HJ, Dewitt MA, et al. Nanoparticle delivery of Cas9 ribonucleoprotein and donor DNA in vivo induces homology-directed DNA repair. Nat Biomed Eng. 2017;1:889–901.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Genovese P, Schiroli G, Escobar G, Tomaso TD, Firrito C, Calabria A, et al. Targeted genome editing in human repopulating haematopoietic stem cells. Nature. 2014;510:235–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Chen A, Koehler AN. Transcription Factor Inhibition: Lessons Learned and Emerging Targets. Trends Mol Med. 2020;26:508–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  241. Bell RJ, Rube HT, Kreig A, Mancini A, Fouse SD, Nagarajan RP, et al. Cancer. The transcription factor GABP selectively binds and activates the mutant TERT promoter in cancer. Science. 2015;348:1036–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. Chimge NO, Baniwal SK, Little GH, Chen YB, Kahn M, Tripathy D, et al. Regulation of breast cancer metastasis by Runx2 and estrogen signaling: the role of SNAI2. Breast Cancer Res. 2011;13:R127.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Cerezo M, Guemiri R, Druillennec S, Girault I, Malka-Mahieu H, Shen S, et al. Translational control of tumor immune escape via the eIF4F-STAT1-PD-L1 axis in melanoma. Nat Med. 2018;24:1877–86.

    Article  CAS  PubMed  Google Scholar 

  244. Boregowda RK, Medina DJ, Markert E, Bryan MA, Chen W, Chen S, et al. The transcription factor RUNX2 regulates receptor tyrosine kinase expression in melanoma. Oncotarget. 2016;7:29689–707.

    Article  PubMed  PubMed Central  Google Scholar 

  245. Rakhra K, Bachireddy P, Zabuawala T, Zeiser R, Xu L, Kopelman A, et al. CD4(+) T cells contribute to the remodeling of the microenvironment required for sustained tumor regression upon oncogene inactivation. Cancer Cell. 2010;18:485–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  246. Krivtsov AV, Twomey D, Feng Z, Stubbs MC, Wang Y, Faber J, et al. Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature. 2006;442:818–22.

    Article  CAS  PubMed  Google Scholar 

  247. Micalizzi DS, Christensen KL, Jedlicka P, Coletta RD, Baron AE, Harrell JC, et al. The Six1 homeoprotein induces human mammary carcinoma cells to undergo epithelial-mesenchymal transition and metastasis in mice through increasing TGF-beta signaling. J Clin Investig. 2009;119:2678–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  248. Xu Y, Poggio M, Jin HY, Shi Z, Forester CM, Wang Y, et al. Translation control of the immune checkpoint in cancer and its therapeutic targeting. Nat Med. 2019;25:301–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  249. Arima Y, Hayashi H, Kamata K, Goto TM, Sasaki M, Kuramochi A, et al. Decreased expression of neurofibromin contributes to epithelial-mesenchymal transition in neurofibromatosis type 1. Exp Dermatol. 2010;19:e136–141.

    Article  PubMed  Google Scholar 

  250. Miller SJ, Rangwala F, Williams J, Ackerman P, Kong S, Jegga AG, et al. Large-scale molecular comparison of human schwann cells to malignant peripheral nerve sheath tumor cell lines and tissues. Cancer Res. 2006;66:2584–91.

    Article  CAS  PubMed  Google Scholar 

  251. Hall A, Choi K, Liu W, Rose J, Zhao C, Yu Y, et al. RUNX represses Pmp22 to drive neurofibromagenesis. Sci Adv. 2019;5:eaau8389.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  252. Antony-Debre I, Paul A, Leite J, Mitchell K, Kim HM, Carvajal LA, et al. Pharmacological inhibition of the transcription factor PU.1 in leukemia. J Clin Investig. 2017;127:4297–313.

    Article  PubMed  PubMed Central  Google Scholar 

  253. Arkin MR, Tang Y, Wells JA. Small-molecule inhibitors of protein-protein interactions: progressing toward the reality. Chem Biol. 2014;21:1102–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  254. Lu G, Middleton RE, Sun H, Naniong M, Ott CJ, Mitsiades CS, et al. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science. 2014;343:305–9.

    Article  CAS  PubMed  Google Scholar 

  255. Fotouhi N, Graves B. Small molecule inhibitors of p53/MDM2 interaction. Curr Top Med Chem. 2005;5:159–65.

    Article  CAS  PubMed  Google Scholar 

  256. Wang S, Kollipara RK, Srivastava N, Li R, Ravindranathan P, Hernandez E, et al. Ablation of the oncogenic transcription factor ERG by deubiquitinase inhibition in prostate cancer. Proc Natl Acad Sci USA. 2014;111:4251–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  257. Pawlak M, Lefebvre P, Staels B. General molecular biology and architecture of nuclear receptors. Curr Top Med Chem. 2012;12:486–504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  258. Nevedomskaya, E, SJ Baumgart, and B Haendler, Recent Advances in Prostate Cancer Treatment and Drug Discovery. Int J Mol Sci. 2018;19:1359.

  259. Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J, Jacobs HM, et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011;146:904–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  260. Mohammad HP, Barbash O, Creasy CL. Targeting epigenetic modifications in cancer therapy: erasing the roadmap to cancer. Nat Med. 2019;25:403–18.

    Article  CAS  PubMed  Google Scholar 

  261. Winter GE, Buckley DL, Paulk J, Roberts JM, Souza A, Dhe-Paganon S, et al. DRUG DEVELOPMENT. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science. 2015;348:1376–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  262. Huang A, Garraway LA, Ashworth A, Weber B. Synthetic lethality as an engine for cancer drug target discovery. Nat Rev Drug Discov. 2020;19:23–38.

    Article  CAS  PubMed  Google Scholar 

  263. Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005;434:913–7.

    Article  CAS  PubMed  Google Scholar 

  264. Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434:917–21.

    Article  CAS  PubMed  Google Scholar 

  265. Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N. Engl J Med. 2009;361:123–34.

    Article  CAS  PubMed  Google Scholar 

  266. Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N. Engl J Med. 2012;366:1382–92.

    Article  CAS  PubMed  Google Scholar 

  267. Tsherniak A, Vazquez F, Montgomery PG, Weir BA, Kryukov G, Cowley GS, et al. Defining a Cancer Dependency Map. Cell. 2017;170:564–576. e516.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  268. Behan FM, Iorio F, Picco G, Goncalves E, Beaver CM, Migliardi G, et al. Prioritization of cancer therapeutic targets using CRISPR-Cas9 screens. Nature. 2019;568:511–6.

    Article  CAS  PubMed  Google Scholar 

  269. Chan EM, Shibue T, McFarland JM, Gaeta B, Ghandi M, Dumont N, et al. WRN helicase is a synthetic lethal target in microsatellite unstable cancers. Nature. 2019;568:551–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  270. Semenova G, Stepanova DS, Deyev SM, Chernoff J. Medium throughput biochemical compound screening identifies novel agents for pharmacotherapy of neurofibromatosis type 1. Biochimie. 2017;135:1–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  271. Williams, KB and DA Largaespada, New Model Systems and the Development of Targeted Therapies for the Treatment of Neurofibromatosis Type 1-Associated Malignant Peripheral Nerve Sheath Tumors. Genes. 2020;11:477.

  272. Meyers RM, Bryan JG, McFarland JM, Weir BA, Sizemore AE, Xu H, et al. Computational correction of copy number effect improves specificity of CRISPR-Cas9 essentiality screens in cancer cells. Nat Genet. 2017;49:1779–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  273. Prahallad A, Sun C, Huang S, Di Nicolantonio F, Salazar R, Zecchin D, et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature. 2012;483:100–3.

    Article  CAS  PubMed  Google Scholar 

  274. Fisher MJ, Shih CS, Rhodes SD, Armstrong AE, Wolters PL, Dombi E, et al. Cabozantinib for neurofibromatosis type 1-related plexiform neurofibromas: a phase 2 trial. Nat Med. 2021;27:165–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  275. Krauthammer M, Kong Y, Bacchiocchi A, Evans P, Pornputtapong N, Wu C, et al. Exome sequencing identifies recurrent mutations in NF1 and RASopathy genes in sun-exposed melanomas. Nat Genet. 2015;47:996–1002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  276. Hodis E, Watson IR, Kryukov GV, Arold ST, Imielinski M, Theurillat JP, et al. A landscape of driver mutations in melanoma. Cell. 2012;150:251–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  277. Opocher G, Schiavi F. Genetics of pheochromocytomas and paragangliomas. Best Pr Res Clin Endocrinol Metab. 2010;24:943–56.

    Article  CAS  Google Scholar 

  278. Welander J, Larsson C, Backdahl M, Hareni N, Sivler T, Brauckhoff M, et al. Integrative genomics reveals frequent somatic NF1 mutations in sporadic pheochromocytomas. Hum Mol Genet. 2012;21:5406–16.

    Article  CAS  PubMed  Google Scholar 

  279. Boudry-Labis E, Roche-Lestienne C, Nibourel O, Boissel N, Terre C, Perot C, et al. Neurofibromatosis-1 gene deletions and mutations in de novo adult acute myeloid leukemia. Am J Hematol. 2013;88:306–11.

    Article  CAS  PubMed  Google Scholar 

  280. Haferlach C, Grossmann V, Kohlmann A, Schindela S, Kern W, Schnittger S, et al. Deletion of the tumor-suppressor gene NF1 occurs in 5% of myeloid malignancies and is accompanied by a mutation in the remaining allele in half of the cases. Leukemia. 2012;26:834–9.

    Article  CAS  PubMed  Google Scholar 

  281. Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, et al. Mutational landscape and significance across 12 major cancer types. Nature. 2013;502:333–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  282. Louis DN. Molecular pathology of malignant gliomas. Annu Rev Pathol. 2006;1:97–117.

    Article  CAS  PubMed  Google Scholar 

  283. Parkin B, Ouillette P, Wang Y, Liu Y, Wright W, Roulston D, et al. NF1 inactivation in adult acute myelogenous leukemia. Clin Cancer Res. 2010;16:4135–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  284. Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, et al. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008;321:1807–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  285. Furukawa K, Yanai N, Fujita M, Harada Y. Novel mutations of neurofibromatosis type 1 gene in small cell lung cancers. Surg Today. 2003;33:323–7.

    Article  CAS  PubMed  Google Scholar 

  286. Ross JS, Wang K, Al-Rohil RN, Nazeer T, Sheehan CE, Otto GA, et al. Advanced urothelial carcinoma: next-generation sequencing reveals diverse genomic alterations and targets of therapy. Mod Pathol. 2014;27:271–80.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

JM is the recipient of the Early Investigator Research Award from the US Department of Defense (W81XWH1910687). LQL held a Career Award for Medical Scientists from the Burroughs Wellcome Fund and is the Thomas L. Shield, M.D. endowed Professor in Dermatology. He is supported by funding from the US Department of Defense, the National Cancer Institute of the NIH (R01 CA166593) and the Developmental and Hyperactive RAS Tumor SPORE (U54 CA196519); the Neurofibromatosis Therapeutic Acceleration Program; the NF1 Research Consortium Fund; and the Giorgio Foundation.

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Authors and Affiliations

  1. Department of Dermatology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, 75390-9069, USA

    Juan Mo, Stefanie L. Moye, Renee M. McKay & Lu Q. Le

  2. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, 75390-9069, USA

    Lu Q. Le

  3. UTSW Comprehensive Neurofibromatosis Clinic, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, 75390-9069, USA

    Lu Q. Le

  4. Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, 75390-9069, USA

    Lu Q. Le

  5. O’Donnell Brain Institute, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, 75390-9069, USA

    Lu Q. Le

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Writing—original draft: JM, SLM, RMM, and LQL; writing—review and editing: JM, RMM, and LQL.

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Mo, J., Moye, S.L., McKay, R.M. et al. Neurofibromin and suppression of tumorigenesis: beyond the GAP. Oncogene 41, 1235–1251 (2022). https://doi.org/10.1038/s41388-021-02156-y

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