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Abstract

Notch receptors influence cellular behavior by participating in a seemingly simple signaling pathway, but outcomes produced by Notch signaling are remarkably varied depending on signal dose and cell context. Here, after briefly reviewing new insights into physiologic mechanisms of Notch signaling in healthy tissues and defects in Notch signaling that contribute to congenital disorders and viral infection, we discuss the varied roles of Notch in cancer, focusing on cell autonomous activities that may be either oncogenic or tumor suppressive.

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2017-01-24
2024-06-17
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Literature Cited

  1. Krebs LT, Xue Y, Norton CR, Shutter JR, Maguire M. 1.  et al. 2000. Notch signaling is essential for vascular morphogenesis in mice. Genes Dev 14:1343–52 [Google Scholar]
  2. Hamada Y, Kadokawa Y, Okabe M, Ikawa M, Coleman JR, Tsujimoto Y. 2.  1999. Mutation in ankyrin repeats of the mouse Notch2 gene induces early embryonic lethality. Development 126:3415–24 [Google Scholar]
  3. Domenga V, Fardoux P, Lacombe P, Monet M, Maciazek J. 3.  et al. 2004. Notch3 is required for arterial identity and maturation of vascular smooth muscle cells. Genes Dev 18:2730–35 [Google Scholar]
  4. Ladi E, Nichols JT, Ge W, Miyamoto A, Yao C. 4.  et al. 2005. The divergent DSL ligand Dll3 does not activate Notch signaling but cell autonomously attenuates signaling induced by other DSL ligands. J. Cell Biol. 170:983–92 [Google Scholar]
  5. Geffers I, Serth K, Chapman G, Jaekel R, Schuster-Gossler K. 5.  et al. 2007. Divergent functions and distinct localization of the Notch ligands DLL1 and DLL3 in vivo. J. Cell Biol. 178:465–76 [Google Scholar]
  6. Chapman G, Sparrow DB, Kremmer E, Dunwoodie SL. 6.  2011. Notch inhibition by the ligand DELTA-LIKE 3 defines the mechanism of abnormal vertebral segmentation in spondylocostal dysostosis. Hum. Mol. Genet. 20:905–16 [Google Scholar]
  7. Hozumi K, Mailhos C, Negishi N, Hirano K, Yahata T. 7.  et al. 2008. Delta-like 4 is indispensable in thymic environment specific for T cell development. J. Exp. Med. 205:2507–13 [Google Scholar]
  8. Radtke F, Wilson A, Stark G, Bauer M, van Meerwijk J. 8.  et al. 1999. Deficient T cell fate specification in mice with an induced inactivation of Notch1. Immunity 10:547–58 [Google Scholar]
  9. Andrawes MB, Xu X, Liu H, Ficarro SB, Marto JA. 9.  et al. 2013. Intrinsic selectivity of Notch 1 for Delta-like 4 over Delta-like 1. J. Biol. Chem. 288:25477–89 [Google Scholar]
  10. Hozumi K, Negishi N, Suzuki D, Abe N, Sotomaru Y. 10.  et al. 2004. Delta-like 1 is necessary for the generation of marginal zone B cells but not T cells in vivo. Nat. Immunol. 5:638–44 [Google Scholar]
  11. Saito T, Chiba S, Ichikawa M, Kunisato A, Asai T. 11.  et al. 2003. Notch2 is preferentially expressed in mature B cells and indispensable for marginal zone B lineage development. Immunity 18:675–85 [Google Scholar]
  12. Logeat F, Bessia C, Brou C, LeBail O, Jarriault S. 12.  et al. 1998. The Notch1 receptor is cleaved constitutively by a furin-like convertase. PNAS 95:8108–12 [Google Scholar]
  13. Rand MD, Grimm LM, Artavanis-Tsakonas S, Patriub V, Blacklow SC. 13.  et al. 2000. Calcium depletion dissociates and activates heterodimeric Notch receptors. Mol. Cell. Biol. 20:1825–35 [Google Scholar]
  14. Gordon WR, Vardar-Ulu D, Histen G, Sanchez-Irizarry C, Aster JC, Blacklow SC. 14.  2007. Structural basis for autoinhibition of Notch. Nat. Struct. Mol. Biol. 14:295–300 [Google Scholar]
  15. Brou C, Logeat F, Gupta N, Bessia C, LeBail O. 15.  et al. 2000. A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE. Mol. Cell 5:207–16 [Google Scholar]
  16. Mumm JS, Schroeter EH, Saxena MT, Griesemer A, Tian X. 16.  et al. 2000. A ligand-induced extracellular cleavage regulates γ-secretase-like proteolytic activation of Notch1. Mol. Cell 5:197–206 [Google Scholar]
  17. Gordon WR, Zimmerman B, He L, Miles LJ, Huang J. 17.  et al. 2015. Mechanical allostery: evidence for a force requirement in the proteolytic activation of Notch. Dev. Cell 33:729–36 [Google Scholar]
  18. Le Borgne R, Remaud S, Hamel S, Schweisguth F. 18.  2005. Two distinct E3 ubiquitin ligases have complementary functions in the regulation of Delta and Serrate signaling in Drosophila. PLOS Biol. 3:e96 [Google Scholar]
  19. Itoh M, Kim CH, Palardy G, Oda T, Jiang YJ. 19.  et al. 2003. Mind bomb is a ubiquitin ligase that is essential for efficient activation of Notch signaling by Delta. Dev. Cell 4:67–82 [Google Scholar]
  20. Gibb DR, El Shikh M, Kang DJ, Rowe WJ, El Sayed R. 20.  et al. 2010. ADAM10 is essential for Notch2-dependent marginal zone B cell development and CD23 cleavage in vivo. J. Exp. Med. 207:623–35 [Google Scholar]
  21. van Tetering G, van Diest P, Verlaan I, van der Wall E, Kopan R, Vooijs M. 21.  2009. Metalloprotease ADAM10 is required for Notch1 site 2 cleavage. J. Biol. Chem. 284:31018–27 [Google Scholar]
  22. Bozkulak EC, Weinmaster G. 22.  2009. Selective use of ADAM10 and ADAM17 in activation of Notch1 signaling. Mol. Cell. Biol. 29:5679–95 [Google Scholar]
  23. Schroeter EH, Kisslinger JA, Kopan R. 23.  1998. Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain. Nature 393:382–86 [Google Scholar]
  24. Struhl G, Grenwald I. 24.  1999. Presenilin is required for activity and nuclear access of Notch in Drosophila. . Nature 398:522–25 [Google Scholar]
  25. Wu L, Aster JC, Blacklow SC, Lake R, Artavanis-Tsakonas S, Griffin JD. 25.  2000. MAML1, a human homologue of Drosophila Mastermind, is a transcriptional co-activator for NOTCH receptors. Nat. Genet. 26:484–89 [Google Scholar]
  26. Oswald F, Tauber B, Dobner T, Bourteele S, Kostezka U. 26.  et al. 2001. p300 acts as a transcriptional coactivator for mammalian Notch-1. Mol. Cell. Biol. 21:7761–74 [Google Scholar]
  27. Mulligan P, Yang F, Di Stefano L, Ji JY, Ouyang J. 27.  et al. 2011. A SIRT1-LSD1 corepressor complex regulates Notch target gene expression and development. Mol. Cell 42:559–60 [Google Scholar]
  28. Yatim A, Benne C, Sobhian B, Laurent-Chabalier S, Deas O. 28.  et al. 2012. NOTCH1 nuclear interactome reveals key regulators of its transcriptional activity and oncogenic function. Mol. Cell 48:445–58 [Google Scholar]
  29. Fryer CJ, White JB, Jones KA. 29.  2004. Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover. Mol. Cell 16:509–20 [Google Scholar]
  30. Bray S, Musisi H, Bienz M. 30.  2005. Bre1 is required for Notch signaling and histone modification. Dev. Cell 8:279–86 [Google Scholar]
  31. Wang H, Zang C, Taing L, Arnett KL, Wong YJ. 31.  et al. 2014. NOTCH1-RBPJ complexes drive target gene expression through dynamic interactions with superenhancers. PNAS 111:705–10 [Google Scholar]
  32. Skalska L, Stojnic R, Li J, Fischer B, Cerda-Moya G. 32.  et al. 2015. Chromatin signatures at Notch-regulated enhancers reveal large-scale changes in H3K56ac upon activation. EMBO J 34:1889–904 [Google Scholar]
  33. Castel D, Mourikis P, Bartels SJ, Brinkman AB, Tajbakhsh S, Stunnenberg HG. 33.  2013. Dynamic binding of RBPJ is determined by Notch signaling status. Genes Dev 27:1059–71 [Google Scholar]
  34. Li N, Fassl A, Chick J, Inuzuka H, Li X. 34.  et al. 2014. Cyclin C is a haploinsufficient tumour suppressor. Nat. Cell Biol. 16:1080–91 [Google Scholar]
  35. O'Neil J, Grim J, Strack P, Rao S, Tibbitts D. 35.  et al. 2007. FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to γ-secretase inhibitors. J. Exp. Med. 204:1813–24 [Google Scholar]
  36. Thompson BJ, Buonamici S, Sulis ML, Palomero T, Vilimas T. 36.  et al. 2007. The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia. J. Exp. Med. 204:1825–35 [Google Scholar]
  37. Espinosa L, Ingles-Esteve J, Aguilera C, Bigas A. 37.  2003. Phosphorylation by glycogen synthase kinase-3β down-regulates Notch activity, a link for Notch and Wnt pathways. J. Biol. Chem. 278:32227–35 [Google Scholar]
  38. Foltz DR, Santiago MC, Berechid BE, Nye JS. 38.  2002. Glycogen synthase kinase-3β modulates Notch signaling and stability. Curr. Biol. 12:1006–11 [Google Scholar]
  39. Mo JS, Kim MY, Han SO, Kim IS, Ann EJ. 39.  et al. 2007. Integrin-linked kinase controls Notch1 signaling by down-regulation of protein stability through Fbw7 ubiquitin ligase. Mol. Cell. Biol. 27:5565–74 [Google Scholar]
  40. Ranganathan P, Vasquez-Del Carpio R, Kaplan FM, Wang H, Gupta A. 40.  et al. 2011. Hierarchical phosphorylation within the ankyrin repeat domain defines a phosphoregulatory loop that regulates Notch transcriptional activity. J. Biol. Chem. 286:28844–57 [Google Scholar]
  41. Hein K, Mittler G, Cizelsky W, Kuhl M, Ferrante F. 41.  et al. 2015. Site-specific methylation of Notch1 controls the amplitude and duration of the Notch1 response. Sci. Signal. 8:ra30 [Google Scholar]
  42. Zheng X, Linke S, Dias JM, Gradin K, Wallis TP. 42.  et al. 2008. Interaction with factor inhibiting HIF-1 defines an additional mode of cross-coupling between the Notch and hypoxia signaling pathways. PNAS 105:3368–73 [Google Scholar]
  43. Guarani V, Deflorian G, Franco CA, Kruger M, Phng LK. 43.  et al. 2011. Acetylation-dependent regulation of endothelial Notch signalling by the SIRT1 deacetylase. Nature 473:234–38 [Google Scholar]
  44. Gerhardt DM, Pajcini KV, D'Altri T, Tu L, Jain R. 44.  et al. 2014. The Notch1 transcriptional activation domain is required for development and reveals a novel role for Notch1 signaling in fetal hematopoietic stem cells. Genes Dev 28:576–93 [Google Scholar]
  45. Okajima T, Xu A, Lei L, Irvine KD. 45.  2005. Chaperone activity of protein O-fucosyltransferase 1 promotes Notch receptor folding. Science 307:1599–603 [Google Scholar]
  46. Stahl M, Uemura K, Ge C, Shi S, Tashima Y, Stanley P. 46.  2008. Roles of Pofut1 and O-fucose in mammalian Notch signaling. J. Biol. Chem. 283:13638–51 [Google Scholar]
  47. Bruckner K, Perez L, Clausen H, Cohen S. 47.  2000. Glycosyltransferase activity of Fringe modulates Notch-Delta interactions. Nature 406:411–15 [Google Scholar]
  48. Luca VC, Jude KM, Pierce NW, Nachury MV, Fischer S, Garcia KC. 48.  2015. Structural basis for Notch1 engagement of Delta-like 4. Science 347:847–53 [Google Scholar]
  49. Acar M, Jafar-Nejad H, Takeuchi H, Rajan A, Ibrani D. 49.  et al. 2008. Rumi is a CAP10 domain glycosyltransferase that modifies Notch and is required for Notch signaling. Cell 132:247–58 [Google Scholar]
  50. Takeuchi H, Fernandez-Valdivia RC, Caswell DS, Nita-Lazar A, Rana NA. 50.  et al. 2011. Rumi functions as both a protein O-glucosyltransferase and a protein O-xylosyltransferase. PNAS 108:16600–5 [Google Scholar]
  51. Yashiro-Ohtani Y, He Y, Ohtani T, Jones ME, Shestova O. 51.  et al. 2009. Pre-TCR signaling inactivates Notch1 transcription by antagonizing E2A. Genes Dev 23:1665–76 [Google Scholar]
  52. Lamar E, Deblandre G, Wettstein D, Gawantka V, Pollet N. 52.  et al. 2001. Nrarp is a novel intracellular component of the Notch signaling pathway. Genes Dev 15:1885–99 [Google Scholar]
  53. Housden BE, Fu AQ, Krejci A, Bernard F, Fischer B. 53.  et al. 2013. Transcriptional dynamics elicited by a short pulse of Notch activation involves feed-forward regulation by E(spl)/Hes genes. PLOS Genet 9:e1003162 [Google Scholar]
  54. Oswald F, Kostezka U, Astrahantseff K, Bourteele S, Dillinger K. 54.  et al. 2002. SHARP is a novel component of the Notch/RBP-Jκ signalling pathway. EMBO J 21:5417–26 [Google Scholar]
  55. Ariyoshi M, Schwabe JW. 55.  2003. A conserved structural motif reveals the essential transcriptional repression function of Spen proteins and their role in developmental signaling. Genes Dev 17:1909–20 [Google Scholar]
  56. Liefke R, Oswald F, Alvarado C, Ferres-Marco D, Mittler G. 56.  et al. 2010. Histone demethylase KDM5A is an integral part of the core Notch-RBP-J repressor complex. Genes Dev 24:590–601 [Google Scholar]
  57. Turkoz M, Townsend RR, Kopan R. 57.  2016. The Notch intracellular domain has an RBPj-independent role during mouse hair follicular development. J. Invest. Dermatol. 136:1106–15 [Google Scholar]
  58. Stoeck A, Lejnine S, Truong A, Pan L, Wang H. 58.  et al. 2014. Discovery of biomarkers predictive of GSI response in triple-negative breast cancer and adenoid cystic carcinoma. Cancer Discov 4:1154–67 [Google Scholar]
  59. Krejci A, Bernard F, Housden BE, Collins S, Bray SJ. 59.  2009. Direct response to Notch activation: signaling crosstalk and incoherent logic. Sci. Signal. 2:ra1 [Google Scholar]
  60. Ditadi A, Sturgeon CM, Tober J, Awong G, Kennedy M. 60.  et al. 2015. Human definitive haemogenic endothelium and arterial vascular endothelium represent distinct lineages. Nat. Cell Biol. 17:580–91 [Google Scholar]
  61. Arnett KL, Hass M, McArthur DG, Ilagan MX, Aster JC. 61.  et al. 2010. Structural and mechanistic insights into cooperative assembly of dimeric Notch transcription complexes. Nat. Struct. Mol. Biol. 17:1312–17 [Google Scholar]
  62. Krejci A, Bray S. 62.  2007. Notch activation stimulates transient and selective binding of Su(H)/CSL to target enhancers. Genes Dev 21:1322–27 [Google Scholar]
  63. Jin YH, Kim H, Ki H, Yang I, Yang N. 63.  et al. 2009. β-catenin modulates the level and transcriptional activity of Notch1/NICD through its direct interaction. Biochim. Biophys. Acta 1793:290–99 [Google Scholar]
  64. Blokzijl A, Dahlqvist C, Reissmann E, Falk A, Moliner A. 64.  et al. 2003. Cross-talk between the Notch and TGF-β signaling pathways mediated by interaction of the Notch intracellular domain with Smad3. J. Cell Biol. 163:723–28 [Google Scholar]
  65. Gustafsson MV, Zheng X, Pereira T, Gradin K, Jin S. 65.  et al. 2005. Hypoxia requires Notch signaling to maintain the undifferentiated cell state. Dev. Cell 9:617–28 [Google Scholar]
  66. Ellisen LW, Bird J, West DC, Soreng AL, Reynolds TC. 66.  et al. 1991. TAN-1, the human homolog of the Drosophila Notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell 66:649–61 [Google Scholar]
  67. Weng AP, Ferrando AA, Lee W, Morris JP, Silverman LB. 67.  et al. 2004. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 306:269–71 [Google Scholar]
  68. Ashworth TD, Pear WS, Chiang MY, Blacklow SC, Mastio J. 68.  et al. 2010. Deletion-based mechanisms of Notch1 activation in T-ALL: key roles for RAG recombinase and a conserved internal translational start site in Notch1. Blood 116:5455–64 [Google Scholar]
  69. Robinson DR, Kalyana-Sundaram S, Wu YM, Shankar S, Cao X. 69.  et al. 2011. Functionally recurrent rearrangements of the MAST kinase and Notch gene families in breast cancer. Nat. Med. 17:1646–51 [Google Scholar]
  70. Frierson HF Jr., Moskaluk CA. 70.  2013. Mutation signature of adenoid cystic carcinoma: evidence for transcriptional and epigenetic reprogramming. J. Clin. Invest. 123:2783–85 [Google Scholar]
  71. Ho AS, Kannan K, Roy DM, Morris LG, Ganly I. 71.  et al. 2013. The mutational landscape of adenoid cystic carcinoma. Nat. Genet. 45:791–98 [Google Scholar]
  72. Stephens PJ, Davies HR, Mitani Y, Van Loo P, Shlien A. 72.  et al. 2013. Whole exome sequencing of adenoid cystic carcinoma. J. Clin. Invest. 123:2965–68 [Google Scholar]
  73. Mosquera JM, Sboner A, Zhang L, Chen CL, Sung YS. 73.  et al. 2013. Novel MIR143-NOTCH fusions in benign and malignant glomus tumors. Genes Chromosom. Cancer 52:1075–87 [Google Scholar]
  74. Wang K, Zhang Q, Li D, Ching K, Zhang C. 74.  et al. 2015. PEST domain mutations in Notch receptors comprise an oncogenic driver segment in triple-negative breast cancer sensitive to a γ-secretase inhibitor. Clin. Cancer Res. 21:1487–96 [Google Scholar]
  75. Di Ianni M, Baldoni S, Rosati E, Ciurnelli R, Cavalli L. 75.  et al. 2009. A new genetic lesion in B-CLL: a NOTCH1 PEST domain mutation. Br. J. Haematol. 146:689–91 [Google Scholar]
  76. Fabbri G, Rasi S, Rossi D, Trifonov V, Khiabanian H. 76.  et al. 2011. Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation. J. Exp. Med. 208:1389–401 [Google Scholar]
  77. Puente XS, Pinyol M, Quesada V, Conde L, Ordonez GR. 77.  et al. 2011. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature 475:101–5 [Google Scholar]
  78. Troen G, Wlodarska I, Warsame A, Hernandez Llodra S, De Wolf-Peeters C, Delabie J. 78.  2008. NOTCH2 mutations in marginal zone lymphoma. Haematologica 93:1107–9 [Google Scholar]
  79. Kiel MJ, Velusamy T, Betz BL, Zhao L, Weigelin HG. 79.  et al. 2012. Whole-genome sequencing identifies recurrent somatic NOTCH2 mutations in splenic marginal zone lymphoma. J. Exp. Med. 209:1553–65 [Google Scholar]
  80. Kridel R, Meissner B, Rogic S, Boyle M, Telenius A. 80.  et al. 2012. Whole transcriptome sequencing reveals recurrent NOTCH1 mutations in mantle cell lymphoma. Blood 119:1963–71 [Google Scholar]
  81. Lee SY, Kumano K, Nakazaki K, Sanada M, Matsumoto A. 81.  et al. 2009. Gain-of-function mutations and copy number increases of Notch2 in diffuse large B-cell lymphoma. Cancer Sci 100:920–26 [Google Scholar]
  82. Lohr JG, Stojanov P, Lawrence MS, Auclair D, Chapuy B. 82.  et al. 2012. Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing. PNAS 109:3879–84 [Google Scholar]
  83. Arcaini L, Rossi D, Lucioni M, Nicola M, Bruscaggin A. 83.  et al. 2015. The NOTCH pathway is recurrently mutated in diffuse large B-cell lymphoma associated with hepatitis C virus infection. Haematologica 100:246–52 [Google Scholar]
  84. Pancewicz J, Taylor JM, Datta A, Baydoun HH, Waldmann TA. 84.  et al. 2010. Notch signaling contributes to proliferation and tumor formation of human T-cell leukemia virus type 1–associated adult T-cell leukemia. PNAS 107:16619–24 [Google Scholar]
  85. Kluk MJ, Ashworth T, Wang H, Knoechel B, Mason EF. 85.  et al. 2013. Gauging NOTCH1 activation in cancer using immunohistochemistry. PLOS ONE 8:e67306 [Google Scholar]
  86. Rosati E, Sabatini R, Rampino G, Tabilio A, Di Ianni M. 86.  et al. 2009. Constitutively activated Notch signaling is involved in survival and apoptosis resistance of B-CLL cells. Blood 113:856–65 [Google Scholar]
  87. del Alamo D, Rouault H, Schweisguth F. 87.  2011. Mechanism and significance of cis-inhibition in Notch signalling. Curr. Biol. 21:R40–47 [Google Scholar]
  88. Sprinzak D, Lakhanpal A, Lebon L, Santat LA, Fontes ME. 88.  et al. 2010. Cis-interactions between Notch and Delta generate mutually exclusive signalling states. Nature 465:86–90 [Google Scholar]
  89. Wang NJ, Sanborn Z, Arnett KL, Bayston LJ, Liao W. 89.  et al. 2011. Loss-of-function mutations in Notch receptors in cutaneous and lung squamous cell carcinoma. PNAS 108:17761–66 [Google Scholar]
  90. Agrawal N, Frederick MJ, Pickering CR, Bettegowda C, Chang K. 90.  et al. 2011. Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science 333:1154–57 [Google Scholar]
  91. Stransky N, Egloff AM, Tward AD, Kostic AD, Cibulskis K. 91.  et al. 2011. The mutational landscape of head and neck squamous cell carcinoma. Science 333:1157–60 [Google Scholar]
  92. Agrawal N, Jiao Y, Bettegowda C, Hutfless SM, Wang Y. 92.  et al. 2012. Comparative genomic analysis of esophageal adenocarcinoma and squamous cell carcinoma. Cancer Discov 2:899–905 [Google Scholar]
  93. 93. The Cancer Genome Atlas Res. Netw. 2012. Comprehensive genomic characterization of squamous cell lung cancers. Nature 489:519–25 [Google Scholar]
  94. George J, Lim JS, Jang SJ, Cun Y, Ozretic L. 94.  et al. 2015. Comprehensive genomic profiles of small cell lung cancer. Nature 524:47–53 [Google Scholar]
  95. Rampias T, Vgenopoulou P, Avgeris M, Polyzos A, Stravodimos K. 95.  et al. 2014. A new tumor suppressor role for the Notch pathway in bladder cancer. Nat. Med. 20:1199–205 [Google Scholar]
  96. 96. The Cancer Genome Atlas Res. Netw. 2015. Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N. Engl. J. Med. 372:2481–98 [Google Scholar]
  97. Nicolas M, Wolfer A, Raj K, Kummer JA, Mill P. 97.  et al. 2003. Notch1 functions as a tumor suppressor in mouse skin. Nat. Genet. 33:416–21 [Google Scholar]
  98. Proweller A, Tu L, Lepore JJ, Cheng L, Lu MM. 98.  et al. 2006. Impaired Notch signaling promotes de novo squamous cell carcinoma formation. Cancer Res 66:7438–44 [Google Scholar]
  99. Kulic I, Robertson G, Chang L, Baker JH, Lockwood WW. 99.  et al. 2015. Loss of the Notch effector RBPJ promotes tumorigenesis. J. Exp. Med. 212:37–52 [Google Scholar]
  100. Tonon G, Modi S, Wu L, Kubo A, Coxon AB. 100.  et al. 2003. t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a Notch signaling pathway. Nat. Genet. 33:208–13 [Google Scholar]
  101. Palomero T, Lim WK, Odom DT, Sulis ML, Real PJ. 101.  et al. 2006. NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth. PNAS 103:18261–66 [Google Scholar]
  102. Sharma VM, Calvo JA, Draheim KM, Cunningham LA, Hermance N. 102.  et al. 2006. Notch1 contributes to mouse T-cell leukemia by directly inducing the expression of c-myc. Mol. . Cell. Biol. 26:8022–31 [Google Scholar]
  103. Weng AP, Millholland JM, Yashiro-Ohtani Y, Arcangeli ML, Lau A. 103.  et al. 2006. c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma. Genes Dev 20:2096–109 [Google Scholar]
  104. Dang CV, Le A, Gao P. 104.  2009. MYC-induced cancer cell energy metabolism and therapeutic opportunities. Clin. Cancer Res. 15:6479–83 [Google Scholar]
  105. Felsher DW, Bishop JM. 105.  1999. Reversible tumorigenesis by MYC in hematopoietic lineages. Mol. Cell 4:199–207 [Google Scholar]
  106. Langenau DM, Traver D, Ferrando AA, Kutok JL, Aster JC. 106.  et al. 2003. Myc-induced T cell leukemia in transgenic zebrafish. Science 299:887–90 [Google Scholar]
  107. Chan SM, Weng AP, Tibshirani R, Aster JC, Utz PJ. 107.  2007. Notch signals positively regulate activity of the mTOR pathway in T-cell acute lymphoblastic leukemia. Blood 110:278–86 [Google Scholar]
  108. Herranz D, Ambesi-Impiombato A, Palomero T, Schnell SA, Belver L. 108.  et al. 2014. A NOTCH1-driven MYC enhancer promotes T cell development, transformation and acute lymphoblastic leukemia. Nat. Med. 20:1130–37 [Google Scholar]
  109. Yashiro-Ohtani Y, Wang H, Zang C, Arnett KL, Bailis W. 109.  et al. 2014. Long-range enhancer activity determines Myc sensitivity to Notch inhibitors in T cell leukemia. PNAS 111:E4946–53 [Google Scholar]
  110. Chiang MY, Wang Q, Gormley AC, Stein SJ, Xu L. 110.  et al. 2016. High selective pressure for Notch1 mutations that induce Myc in T-cell acute lymphoblastic leukemia. Blood. 1282229–40
  111. Knoechel B, Roderick JE, Williamson KE, Zhu J, Lohr JG. 111.  et al. 2014. An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia. Nat. Genet. 46:364–70 [Google Scholar]
  112. Zuber J, Shi J, Wang E, Rappaport AR, Herrmann H. 112.  et al. 2011. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature 478:524–28 [Google Scholar]
  113. Roderick JE, Tesell J, Shultz LD, Brehm MA, Greiner DL. 113.  et al. 2014. c-Myc inhibition prevents leukemia initiation in mice and impairs the growth of relapsed and induction failure pediatric T-ALL cells. Blood 123:1040–50 [Google Scholar]
  114. Palomero T, Sulis ML, Cortina M, Real PJ, Barnes K. 114.  et al. 2007. Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat. Med. 13:1203–10 [Google Scholar]
  115. Boudil A, Matei IR, Shih H-Y, Bogdanoski G, Yuan JS. 115.  et al. 2015. IL-7 coordinates proliferation, differentiation and Tcra recombination during thymocyte β-selection. Nat. Immunol. 16:397–405 [Google Scholar]
  116. Trimarchi T, Bilal E, Ntziachristos P, Fabbri G, Dalla-Favera R. 116.  et al. 2014. Genome-wide mapping and characterization of Notch-regulated long noncoding RNAs in acute leukemia. Cell 158:593–606 [Google Scholar]
  117. Jitschin R, Braun M, Qorraj M, Saul D, Le Blanc K. 117.  et al. 2015. Stromal cell-mediated glycolytic switch in CLL cells involves Notch-c-Myc signaling. Blood 125:3432–36 [Google Scholar]
  118. Klinakis A, Szabolcs M, Politi K, Kiaris H, Artavanis-Tsakonas S, Efstratiadis A. 118.  2006. Myc is a Notch1 transcriptional target and a requisite for Notch1-induced mammary tumorigenesis in mice. PNAS 103:9262–67 [Google Scholar]
  119. Zhao B, Zou JY, Wang H, Johannsen E, Peng C-W. 119.  et al. 2011. Epstein-Barr virus exploits intrinsic B-lymphocyte transcription programs to achieve immortal cell growth. PNAS 108:14902–7 [Google Scholar]
  120. Knoechel B, Bhatt A, Pan L, Pedamallu CS, Severson E. 120.  et al. 2015. Complete hematologic response of early T-cell progenitor acute lymphoblastic leukemia to the γ-secretase inhibitor BMS-906024: genetic and epigenetic findings in an outlier case. Cold Spring Harb. Mol. Case Stud. 1:a000539 [Google Scholar]
  121. Sahlgren C, Gustafsson MV, Jin S, Poellinger L, Lendahl U. 121.  2008. Notch signaling mediates hypoxia-induced tumor cell migration and invasion. PNAS 105:6392–97 [Google Scholar]
  122. Manning BD, Cantley LC. 122.  2007. AKT/PKB signaling: navigating downstream. Cell 129:1261–74 [Google Scholar]
  123. Espinosa L, Cathelin S, D'Altri T, Trimarchi T, Statnikov A. 123.  et al. 2010. The Notch/Hes1 pathway sustains NF-κB activation through CYLD repression in T cell leukemia. Cancer Cell 18:268–81 [Google Scholar]
  124. Vacca A, Felli MP, Palermo R, Di Mario G, Calce A. 124.  et al. 2006. Notch3 and pre-TCR interaction unveils distinct NF-κB pathways in T-cell development and leukemia. EMBO J 25:1000–8 [Google Scholar]
  125. Shin HM, Minter LM, Cho OH, Gottipati S, Fauq AH. 125.  et al. 2006. Notch1 augments NF-κB activity by facilitating its nuclear retention. EMBO J 25:129–38 [Google Scholar]
  126. Deftos ML, He YW, Ojala EW, Bevan MJ. 126.  1998. Correlating Notch signaling with thymocyte maturation. Immunity 9:777–86 [Google Scholar]
  127. Piovan E, Yu J, Tosello V, Herranz D, Ambesi-Impiombato A. 127.  et al. 2013. Direct reversal of glucocorticoid resistance by AKT inhibition in acute lymphoblastic leukemia. Cancer Cell 24:766–76 [Google Scholar]
  128. Real PJ, Tosello V, Palomero T, Castillo M, Hernando E. 128.  et al. 2009. γ-Secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia. Nat. Med. 15:50–58 [Google Scholar]
  129. Gutierrez A, Pan L, Groen RW, Baleydier F, Kentsis A. 129.  et al. 2014. Phenothiazines induce PP2A-mediated apoptosis in T cell acute lymphoblastic leukemia. J. Clin. Invest. 124:644–55 [Google Scholar]
  130. Martz CA, Ottina KA, Singleton KR, Jasper JS, Wardell SE. 130.  et al. 2014. Systematic identification of signaling pathways with potential to confer anticancer drug resistance. Sci. Signal. 7:ra121 [Google Scholar]
  131. Lafkas D, Shelton A, Chiu C, de Leon Boenig G, Chen Y. 131.  et al. 2015. Therapeutic antibodies reveal Notch control of transdifferentiation in the adult lung. Nature 528:127–31 [Google Scholar]
  132. Drier Y, Cotton MJ, Williamson KE, Gillespie SM, Ryan RJ. 132.  et al. 2016. An oncogenic MYB feedback loop drives alternate cell fates in adenoid cystic carcinoma. Nat. Genet. 48:265–72 [Google Scholar]
  133. Crum CP, McKeon FD. 133.  2010. p63 in epithelial survival, germ cell surveillance, and neoplasia. Annu. Rev. Pathol. 5:349–71 [Google Scholar]
  134. Nguyen BC, Lefort K, Mandinova A, Antonini D, Devgan V. 134.  et al. 2006. Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation. Genes Dev 20:1028–42 [Google Scholar]
  135. Blanpain C, Lowry WE, Pasolli HA, Fuchs E. 135.  2006. Canonical notch signaling functions as a commitment switch in the epidermal lineage. Genes Dev 20:3022–35 [Google Scholar]
  136. Brimer N, Lyons C, Wallberg AE, Vande Pol SB. 136.  2012. Cutaneous papillomavirus E6 oncoproteins associate with MAML1 to repress transactivation and NOTCH signaling. Oncogene 31:4639–46 [Google Scholar]
  137. Tan MJ, White EA, Sowa ME, Harper JW, Aster JC, Howley PM. 137.  2012. Cutaneous β-human papillomavirus E6 proteins bind Mastermind-like coactivators and repress Notch signaling. PNAS 109:E1473–80 [Google Scholar]
  138. Meyers JM, Spangle JM, Munger K. 138.  2013. The human papillomavirus type 8 E6 protein interferes with NOTCH activation during keratinocyte differentiation. J. Virol. 87:4762–67 [Google Scholar]
  139. Alcolea MP, Greulich P, Wabik A, Frede J, Simons BD, Jones PH. 139.  2014. Differentiation imbalance in single oesophageal progenitor cells causes clonal immortalization and field change. Nat. Cell Biol. 16:615–22 [Google Scholar]
  140. Martincorena I, Roshan A, Gerstung M, Ellis P, Van Loo P. 140.  et al. 2015. High burden and pervasive positive selection of somatic mutations in normal human skin. Science 348:880–86 [Google Scholar]
  141. Demehri S, Turkoz A, Kopan R. 141.  2009. Epidermal Notch1 loss promotes skin tumorigenesis by impacting the stromal microenvironment. Cancer Cell 16:55–66 [Google Scholar]
  142. Hu B, Castillo E, Harewood L, Ostano P, Reymond A. 142.  et al. 2012. Multifocal epithelial tumors and field cancerization from loss of mesenchymal CSL signaling. Cell 149:1207–20 [Google Scholar]
  143. Shimojo H, Ohtsuka T, Kageyama R. 143.  2008. Oscillations in Notch signaling regulate maintenance of neural progenitors. Neuron 58:52–64 [Google Scholar]
  144. Imayoshi I, Sakamoto M, Yamaguchi M, Mori K, Kageyama R. 144.  2010. Essential roles of Notch signaling in maintenance of neural stem cells in developing and adult brains. J. Neurosci. 30:3489–98 [Google Scholar]
  145. Fan X, Khaki L, Zhu TS, Soules ME, Talsma CE. 145.  et al. 2010. NOTCH pathway blockade depletes CD133-positive glioblastoma cells and inhibits growth of tumor neurospheres and xenografts. Stem Cells 28:5–16 [Google Scholar]
  146. Zhu TS, Costello MA, Talsma CE, Flack CG, Crowley JG. 146.  et al. 2011. Endothelial cells create a stem cell niche in glioblastoma by providing NOTCH ligands that nurture self-renewal of cancer stem-like cells. Cancer Res 71:6061–72 [Google Scholar]
  147. Jiang LY, Zhang XL, Du P, Zheng JH. 147.  2011. γ-Secretase inhibitor, DAPT inhibits self-renewal and stemness maintenance of ovarian cancer stem-like cells in vitro. Chin. J. Cancer Res. 23:140–46 [Google Scholar]
  148. McAuliffe SM, Morgan SL, Wyant GA, Tran LT, Muto KW. 148.  et al. 2012. Targeting Notch, a key pathway for ovarian cancer stem cells, sensitizes tumors to platinum therapy. PNAS 109:E2939–48 [Google Scholar]
  149. Dontu G, Jackson KW, McNicholas E, Kawamura MJ, Abdallah WM, Wicha MS. 149.  2004. Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells. Breast Cancer Res 6:R605–15 [Google Scholar]
  150. D'Angelo RC, Ouzounova M, Davis A, Choi D, Tchuenkam SM. 150.  et al. 2015. Notch reporter activity in breast cancer cell lines identifies a subset of cells with stem cell activity. Mol. Cancer Ther. 14:779–87 [Google Scholar]
  151. Abravanel DL, Belka GK, Pan TC, Pant DK, Collins MA. 151.  et al. 2015. Notch promotes recurrence of dormant tumor cells following HER2/neu-targeted therapy. J. Clin. Invest. 125:2484–96 [Google Scholar]
  152. Kuhnert F, Chen G, Coetzee S, Thambi N, Hickey C. 152.  et al. 2015. Dll4 Blockade in stromal cells mediates antitumor effects in preclinical models of ovarian cancer. Cancer Res 75:4086–96 [Google Scholar]
  153. Lu J, Ye X, Fan F, Xia L, Bhattacharya R. 153.  et al. 2013. Endothelial cells promote the colorectal cancer stem cell phenotype through a soluble form of Jagged-1. Cancer Cell 23:171–85 [Google Scholar]
  154. Androutsellis-Theotokis A, Leker RR, Soldner F, Hoeppner DJ, Ravin R. 154.  et al. 2006. Notch signalling regulates stem cell numbers in vitro and in vivo. Nature 442:823–26 [Google Scholar]
  155. Timmerman LA, Grego-Bessa J, Raya A, Bertran E, Perez-Pomares JM. 155.  et al. 2004. Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation. Genes Dev 18:99–115 [Google Scholar]
  156. Niessen K, Fu Y, Chang L, Hoodless PA, McFadden D, Karsan A. 156.  2008. Slug is a direct Notch target required for initiation of cardiac cushion cellularization. J. Cell Biol. 182:315–25 [Google Scholar]
  157. Ye X, Weinberg RA. 157.  2015. Epithelial-mesenchymal plasticity: a central regulator of cancer progression. Trends Cell Biol 25:675–86 [Google Scholar]
  158. Brabletz S, Bajdak K, Meidhof S, Burk U, Niedermann G. 158.  et al. 2011. The ZEB1/miR-200 feedback loop controls Notch signalling in cancer cells. EMBO J 30:770–82 [Google Scholar]
  159. Chanrion M, Kuperstein I, Barriere C, El Marjou F, Cohen D. 159.  et al. 2014. Concomitant Notch activation and p53 deletion trigger epithelial-to-mesenchymal transition and metastasis in mouse gut. Nat. Commun. 5:5005 [Google Scholar]
  160. Leong KG, Niessen K, Kulic I, Raouf A, Eaves C. 160.  et al. 2007. Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin. J. Exp. Med. 204:2935–48 [Google Scholar]
  161. Sonoshita M, Aoki M, Fuwa H, Aoki K, Hosogi H. 161.  et al. 2011. Suppression of colon cancer metastasis by Aes through inhibition of Notch signaling. Cancer Cell 19:125–37 [Google Scholar]
  162. Sonoshita M, Itatani Y, Kakizaki F, Sakimura K, Terashima T. 162.  et al. 2015. Promotion of colorectal cancer invasion and metastasis through activation of NOTCH-DAB1-ABL-RHOGEF protein TRIO. Cancer Discov 5:198–211 [Google Scholar]
  163. Xing F, Kobayashi A, Okuda H, Watabe M, Pai SK. 163.  et al. 2013. Reactive astrocytes promote the metastatic growth of breast cancer stem-like cells by activating Notch signalling in brain. EMBO Mol. Med. 5:384–96 [Google Scholar]
  164. Yang Y, Ahn YH, Gibbons DL, Zang Y, Lin W. 164.  et al. 2011. The Notch ligand Jagged2 promotes lung adenocarcinoma metastasis through a miR-200-dependent pathway in mice. J. Clin. Invest. 121:1373–85 [Google Scholar]
  165. Capaccione KM, Pine SR. 165.  2013. The Notch signaling pathway as a mediator of tumor survival. Carcinogenesis 34:1420–30 [Google Scholar]
  166. Domingo-Domenech J, Vidal SJ, Rodriguez-Bravo V, Castillo-Martin M, Quinn SA. 166.  et al. 2012. Suppression of acquired docetaxel resistance in prostate cancer through depletion of Notch- and Hedgehog-dependent tumor-initiating cells. Cancer Cell 22:373–88 [Google Scholar]
  167. Wang Z, Li Y, Ahmad A, Azmi AS, Banerjee S. 167.  et al. 2010. Targeting Notch signaling pathway to overcome drug resistance for cancer therapy. Biochim. Biophys. Acta 1806:258–67 [Google Scholar]
  168. Xie M, He CS, Wei SH, Zhang L. 168.  2013. Notch-1 contributes to epidermal growth factor receptor tyrosine kinase inhibitor acquired resistance in non-small cell lung cancer in vitro and in vivo. Eur. J. Cancer 49:3559–72 [Google Scholar]
  169. Fischer KR, Durrans A, Lee S, Sheng J, Li F. 169.  et al. 2015. Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature 527:472–76 [Google Scholar]
  170. Zheng X, Carstens JL, Kim J, Scheible M, Kaye J. 170.  et al. 2015. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 527:525–30 [Google Scholar]
  171. Sethi N, Dai X, Winter CG, Kang Y. 171.  2011. Tumor-derived Jagged1 promotes osteolytic bone metastasis of breast cancer by engaging Notch signaling in bone cells. Cancer Cell 19:192–205 [Google Scholar]
  172. Gottlieb TM, Leal JF, Seger R, Taya Y, Oren M. 172.  2002. Cross-talk between Akt, p53 and Mdm2: possible implications for the regulation of apoptosis. Oncogene 21:1299–303 [Google Scholar]
  173. Beverly LJ, Felsher DW, Capobianco AJ. 173.  2005. Suppression of p53 by Notch in lymphomagenesis: implications for initiation and regression. Cancer Res 65:7159–68 [Google Scholar]
  174. Dotto GP. 174.  2009. Crosstalk of Notch with p53 and p63 in cancer growth control. Nat. Rev. Cancer 9:587–95 [Google Scholar]
  175. Gridley T. 175.  2007. Notch signaling in vascular development and physiology. Development 134:2709–18 [Google Scholar]
  176. Kuhnert F, Kirshner JR, Thurston G. 176.  2011. Dll4-Notch signaling as a therapeutic target in tumor angiogenesis. Vasc. Cell 3:20 [Google Scholar]
  177. Ridgway J, Zhang G, Wu Y, Stawicki S, Liang WC. 177.  et al. 2006. Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature 444:1083–87 [Google Scholar]
  178. Bailis W, Yashiro-Ohtani Y, Fang TC, Hatton RD, Weaver CT. 178.  et al. 2013. Notch simultaneously orchestrates multiple helper T cell programs independently of cytokine signals. Immunity 39:148–59 [Google Scholar]
  179. Xu H, Zhu J, Smith S, Foldi J, Zhao B. 179.  et al. 2012. Notch-RBP-J signaling regulates the transcription factor IRF8 to promote inflammatory macrophage polarization. Nat. Immunol. 13:642–50 [Google Scholar]
  180. Xu J, Chi F, Guo T, Punj V, Lee WN. 180.  et al. 2015. NOTCH reprograms mitochondrial metabolism for proinflammatory macrophage activation. J. Clin. Invest. 125:1579–90 [Google Scholar]
  181. Tran IT, Sandy AR, Carulli AJ, Ebens C, Chung J. 181.  et al. 2013. Blockade of individual Notch ligands and receptors controls graft-versus-host disease. J. Clin. Invest. 123:1590–604 [Google Scholar]
  182. Fasnacht N, Huang HY, Koch U, Favre S, Auderset F. 182.  et al. 2014. Specific fibroblastic niches in secondary lymphoid organs orchestrate distinct Notch-regulated immune responses. J. Exp. Med. 211:2265–79 [Google Scholar]
  183. Klinakis A, Lobry C, Abdel-Wahab O, Oh P, Haeno H. 183.  et al. 2011. A novel tumour-suppressor function for the Notch pathway in myeloid leukaemia. Nature 473:230–33 [Google Scholar]
  184. Kode A, Manavalan JS, Mosialou I, Bhagat G, Rathinam CV. 184.  et al. 2014. Leukaemogenesis induced by an activating β-catenin mutation in osteoblasts. Nature 506:240–44 [Google Scholar]
  185. Atlas TCG. 185.  2011. Integrated genomic analyses of ovarian carcinoma. Nature 474:609–15 [Google Scholar]
  186. Golan T, Messer AR, Amitai-Lange A, Melamed Z, Ohana R. 186.  et al. 2015. Interactions of melanoma cells with distal keratinocytes trigger metastasis via Notch signaling inhibition of MITF. Mol. Cell 59:664–76 [Google Scholar]
  187. Gurney A, Hoey T. 187.  2011. Anti-DLL4, a cancer therapeutic with multiple mechanisms of action. Vasc. Cell 3:18 [Google Scholar]
  188. Li K, Li Y, Wu W, Gordon WR, Chang DW. 188.  et al. 2008. Modulation of Notch signaling by antibodies specific for the extracellular negative regulatory region of NOTCH3. J. Biol. Chem. 283:8046–54 [Google Scholar]
  189. Noguera-Troise I, Daly C, Papadopoulos NJ, Coetzee S, Boland P. 189.  et al. 2006. Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature 444:1032–37 [Google Scholar]
  190. Wu Y, Cain-Hom C, Choy L, Hagenbeek TJ, de Leon GP. 190.  et al. 2010. Therapeutic antibody targeting of individual Notch receptors. Nature 464:1052–57 [Google Scholar]
  191. Bernasconi-Elias P, Hu T, Jenkins D, Firestone B, Gans S. 191.  et al. 2016. Characterization of activating mutations of NOTCH3 in T-cell acute lymphoblastic leukemia and anti-leukemic activity of NOTCH3 inhibitory antibodies. Oncogene 35:6077–86 [Google Scholar]
  192. Kamath BM, Bauer RC, Loomes KM, Chao G, Gerfen J. 192.  et al. 2012. NOTCH2 mutations in Alagille syndrome. J. Med. Genet 49138–44 [Google Scholar]
  193. Oda T, Elkahloun AG, Pike BL, Okajima K, Krantz ID. 193.  et al. 1997. Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat. Genet. 16:235–42 [Google Scholar]
  194. Joutel A, Corpechot C, Ducros A, Vahedi K, Chabriat H. 194.  et al. 1996. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 383:707–10 [Google Scholar]
  195. Garg V, Muth AN, Ransom JF, Schluterman MK, Barnes R. 195.  et al. 2005. Mutations in NOTCH1 cause aortic valve disease. Nature 437:270–74 [Google Scholar]
  196. Simpson MA, Irving MD, Asilmaz E, Gray MJ, Dafou D. 196.  et al. 2011. Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss. Nat. Genet. 43:303–5 [Google Scholar]
  197. Hassed SJ, Wiley GB, Wang S, Lee JY, Li S. 197.  et al. 2012. RBPJ mutations identified in two families affected by Adams-Oliver syndrome. Am. J. Hum. Genet. 91:391–95 [Google Scholar]
  198. Stittrich AB, Lehman A, Bodian DL, Ashworth J, Zong Z. 198.  et al. 2014. Mutations in NOTCH1 cause Adams-Oliver syndrome. Am. J. Hum. Genet. 95:275–84 [Google Scholar]
  199. Meester JA, Southgate L, Stittrich AB, Venselaar H, Beekmans SJ. 199.  et al. 2015. Heterozygous loss-of-function mutations in DLL4 cause Adams-Oliver syndrome. Am. J. Hum. Genet. 97:475–82 [Google Scholar]
  200. Bulman MP, Kusumi K, Frayling TM, McKeown C, Garrett C. 200.  et al. 2000. Mutations in the human Delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis. Nat. Genet. 24:438–41 [Google Scholar]
  201. Basmanav FB, Oprisoreanu AM, Pasternack SM, Thiele H, Fritz G. 201.  et al. 2014. Mutations in POGLUT1, encoding protein O-glucosyltransferase 1, cause autosomal-dominant Dowling-Degos disease. Am. J. Hum. Genet. 94:135–43 [Google Scholar]
  202. Li CR, Brooks YS, Jia WX, Wang DG, Xiao XM. 202.  et al. 2016. Pathogenicity of POFUT1 mutations in two Chinese families with Dowling-Degos disease. J. Eur. Acad. Dermatol. Venereol. 30:e79–81 [Google Scholar]
  203. Hsieh JJ, Hayward SD. 203.  1995. Masking of the CBF1/RBPJ κ transcriptional repression domain by Epstein-Barr virus EBNA2. Science 268:560–63 [Google Scholar]
  204. Robertson ES, Lin J, Kieff E. 204.  1996. The amino-terminal domains of Epstein-Barr virus nuclear proteins 3A, 3B, and 3C interact with RBPJ(κ). J. Virol. 70:3068–74 [Google Scholar]
  205. Ansieau S, Strobl LJ, Leutz A. 205.  2001. Activation of the Notch-regulated transcription factor CBF1/RBP-Jκ through the 13SE1A oncoprotein. Genes Dev 15:380–85 [Google Scholar]
  206. Persson LM, Wilson AC. 206.  2010. Wide-scale use of Notch signaling factor CSL/RBP-Jκ in RTA-mediated activation of Kaposi's sarcoma-associated herpesvirus lytic genes. J. Virol. 84:1334–47 [Google Scholar]
  207. Xu X, Choi SH, Hu T, Tiyanont K, Habets R. 207.  et al. 2015. Insights into autoregulation of Notch3 from structural and functional studies of its negative regulatory region. Structure 23:1227–35 [Google Scholar]
  208. Van Vlierberghe P, Ambesi-Impiombato A, Perez-Garcia A, Haydu JE, Rigo I. 208.  et al. 2011. ETV6 mutations in early immature human T cell leukemias. J. Exp. Med. 208:2571–79 [Google Scholar]
  209. Zhang J, Ding L, Holmfeldt L, Wu G, Heatley SL. 209.  et al. 2012. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature 481:157–63 [Google Scholar]
  210. Neumann M, Heesch S, Schlee C, Schwartz S, Gokbuget N. 210.  et al. 2013. Whole-exome sequencing in adult ETP-ALL reveals a high rate of DNMT3A mutations. Blood 121:4749–52 [Google Scholar]
  211. Puente XS, Bea S, Valdes-Mas R, Villamor N, Gutierrez-Abril J. 211.  et al. 2015. Non-coding recurrent mutations in chronic lymphocytic leukaemia. Nature 526:519–24 [Google Scholar]
  212. Bea S, Valdes-Mas R, Navarro A, Salaverria I, Martin-Garcia D. 212.  et al. 2013. Landscape of somatic mutations and clonal evolution in mantle cell lymphoma. PNAS 110:18250–55 [Google Scholar]
  213. Rossi D, Trifonov V, Fangazio M, Bruscaggin A, Rasi S. 213.  et al. 2012. The coding genome of splenic marginal zone lymphoma: activation of NOTCH2 and other pathways regulating marginal zone development. J. Exp. Med. 209:1537–51 [Google Scholar]
  214. Martinez D, Navarro A, Martinez-Trillos A, Molina-Urra R, Gonzalez-Farre B. 214.  et al. 2016. NOTCH1, TP53, and MAP2K1 mutations in splenic diffuse red pulp small B-cell lymphoma are associated with progressive disease. Am. J. Surg. Pathol. 40:192–201 [Google Scholar]
  215. Shimizu D, Taki T, Utsunomiya A, Nakagawa H, Nomura K. 215.  et al. 2007. Detection of NOTCH1 mutations in adult T-cell leukemia/lymphoma and peripheral T-cell lymphoma. Int. J. Hematol. 85:212–18 [Google Scholar]
  216. South AP, Purdie KJ, Watt SA, Haldenby S, den Breems NY. 216.  et al. 2014. NOTCH1 mutations occur early during cutaneous squamous cell carcinogenesis. J. Invest. Dermatol. 134:2630–38 [Google Scholar]
  217. Durinck S, Ho C, Wang NJ, Liao W, Jakkula LR. 217.  et al. 2011. Temporal dissection of tumorigenesis in primary cancers. Cancer Discov 1:137–43 [Google Scholar]
  218. Song Y, Li L, Ou Y, Gao Z, Li E. 218.  et al. 2014. Identification of genomic alterations in oesophageal squamous cell cancer. Nature 509:91–95 [Google Scholar]
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