1932

Abstract

Viral infection underlies a significant share of the global cancer burden. Merkel cell polyomavirus (MCPyV) is the newest member of the human oncogenic virus family. Its discovery over a decade ago marked the beginning of an exciting era in human tumor virology. Since then, significant evidence has emerged to support the etiologic role of MCPyV in Merkel cell carcinoma (MCC), an extremely lethal form of skin cancer. MCPyV infection is widespread in the general population. MCC diagnoses have tripled over the past 20 years, but effective treatments are currently lacking. In this review, we highlight recent discoveries that have shaped our understanding of MCPyV oncogenic mechanism and host cellular tropism, as well as the molecular events occurring in the viral infectious life cycle. These insights will guide future efforts in developing novel virus-targeted therapeutic strategies for treating the devastating human cancers associated with this new tumorigenic virus.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-virology-011720-121757
2020-09-29
2024-03-28
Loading full text...

Full text loading...

/deliver/fulltext/virology/7/1/annurev-virology-011720-121757.html?itemId=/content/journals/10.1146/annurev-virology-011720-121757&mimeType=html&fmt=ahah

Literature Cited

  1. 1. 
    Feng H, Shuda M, Chang Y, Moore PS 2008. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science 319:1096–100
    [Google Scholar]
  2. 2. 
    Gjoerup O, Chang Y. 2010. Update on human polyomaviruses and cancer. Advances in Cancer Research FVW George, K George 1–51 Cambridge, MA: Academic
    [Google Scholar]
  3. 3. 
    Chang Y, Moore PS. 2012. Merkel cell carcinoma: a virus-induced human cancer. Annu. Rev. Pathol. 7:123–44
    [Google Scholar]
  4. 4. 
    Vilchez RA, Butel JS. 2004. Emergent human pathogen simian virus 40 and its role in cancer. Clin. Microbiol. Rev. 17:495–508
    [Google Scholar]
  5. 5. 
    Abend JR, Jiang M, Imperiale MJ 2009. BK virus and human cancer: innocent until proven guilty. Semin. Cancer Biol. 19:252–60
    [Google Scholar]
  6. 6. 
    Lemos B, Nghiem P. 2007. Merkel cell carcinoma: more deaths but still no pathway to blame. J. Invest. Dermatol. 127:2100–3
    [Google Scholar]
  7. 7. 
    Harms PW. 2017. Update on Merkel cell carcinoma. Clin. Lab. Med. 37:485–501
    [Google Scholar]
  8. 8. 
    Agelli M, Clegg LX, Becker JC, Rollison DE 2010. The etiology and epidemiology of Merkel cell carcinoma. Curr. Probl. Cancer 34:14–37
    [Google Scholar]
  9. 9. 
    Agelli M, Clegg LX. 2003. Epidemiology of primary Merkel cell carcinoma in the United States. J. Am. Acad. Dermatol. 49:832–41
    [Google Scholar]
  10. 10. 
    Harms KL, Healy MA, Nghiem P, Sober AJ, Johnson TM et al. 2016. Analysis of prognostic factors from 9387 Merkel cell carcinoma cases forms the basis for the new 8th edition AJCC staging system. Ann. Surg. Oncol. 23:3564–71
    [Google Scholar]
  11. 11. 
    Paulson KG, Park SY, Vandeven NA, Lachance K, Thomas H et al. 2018. Merkel cell carcinoma: current US incidence and projected increases based on changing demographics. J. Am. Acad. Dermatol. 78:457–63
    [Google Scholar]
  12. 12. 
    Engels EA, Frisch M, Goedert JJ, Biggar RJ, Miller RW 2002. Merkel cell carcinoma and HIV infection. Lancet 359:497–98
    [Google Scholar]
  13. 13. 
    Heath M, Jaimes N, Lemos B, Mostaghimi A, Wang LC et al. 2008. Clinical characteristics of Merkel cell carcinoma at diagnosis in 195 patients: the AEIOU features. J. Am. Acad. Dermatol. 58:375–81
    [Google Scholar]
  14. 14. 
    Miller RW, Rabkin CS. 1999. Merkel cell carcinoma and melanoma: etiological similarities and differences. Cancer Epidemiol. Biomarkers Prev. 8:153–58
    [Google Scholar]
  15. 15. 
    Lunder EJ, Stern RS. 1998. Merkel-cell carcinomas in patients treated with methoxsalen and ultraviolet A radiation. N. Engl. J. Med. 339:1247–48
    [Google Scholar]
  16. 16. 
    Clarke CA, Robbins HA, Tatalovich Z, Lynch CF, Pawlish KS et al. 2015. Risk of Merkel cell carcinoma after solid organ transplantation. J. Natl. Cancer Inst. 107:dju382
    [Google Scholar]
  17. 17. 
    Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J et al. 1994. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science 266:1865–69
    [Google Scholar]
  18. 18. 
    Liu W, MacDonald M, You J 2016. Merkel cell polyomavirus infection and Merkel cell carcinoma. Curr. Opin. Virol. 20:20–27
    [Google Scholar]
  19. 19. 
    Buck CB, Van Doorslaer K, Peretti A, Geoghegan EM, Tisza MJ et al. 2016. The ancient evolutionary history of polyomaviruses. PLOS Pathog 12:e1005574
    [Google Scholar]
  20. 20. 
    Leendertz FH, Scuda N, Cameron KN, Kidega T, Zuberbuhler K et al. 2011. African great apes are naturally infected with polyomaviruses closely related to Merkel cell polyomavirus. J. Virol. 85:916–24
    [Google Scholar]
  21. 21. 
    Harrison CJ, Meinke G, Kwun HJ, Rogalin H, Phelan PJ et al. 2011. Asymmetric assembly of Merkel cell polyomavirus large T-antigen origin binding domains at the viral origin. J. Mol. Biol. 409:529–42
    [Google Scholar]
  22. 22. 
    Kwun HJ, Guastafierro A, Shuda M, Meinke G, Bohm A et al. 2009. The minimum replication origin of Merkel cell polyomavirus has a unique large T-antigen loading architecture and requires small T-antigen expression for optimal replication. J. Virol. 83:12118–28
    [Google Scholar]
  23. 23. 
    Carter JJ, Daugherty MD, Qi X, Bheda-Malge A, Wipf GC et al. 2013. Identification of an overprinting gene in Merkel cell polyomavirus provides evolutionary insight into the birth of viral genes. PNAS 110:12744–49
    [Google Scholar]
  24. 24. 
    Seo GJ, Chen CJ, Sullivan CS 2009. Merkel cell polyomavirus encodes a microRNA with the ability to autoregulate viral gene expression. Virology 383:183–87
    [Google Scholar]
  25. 25. 
    Lee S, Paulson KG, Murchison EP, Afanasiev OK, Alkan C et al. 2011. Identification and validation of a novel mature microRNA encoded by the Merkel cell polyomavirus in human Merkel cell carcinomas. J. Clin. Virol. 52:272–75
    [Google Scholar]
  26. 26. 
    Schowalter RM, Pastrana DV, Buck CB 2011. Glycosaminoglycans and sialylated glycans sequentially facilitate Merkel cell polyomavirus infectious entry. PLOS Pathog 7:e1002161
    [Google Scholar]
  27. 27. 
    Schowalter RM, Reinhold WC, Buck CB 2012. Entry tropism of BK and Merkel cell polyomaviruses in cell culture. PLOS ONE 7:e42181
    [Google Scholar]
  28. 28. 
    Schowalter RM, Buck CB. 2013. The Merkel cell polyomavirus minor capsid protein. PLOS Pathog 9:e1003558
    [Google Scholar]
  29. 29. 
    Nicol JT, Robinot R, Carpentier A, Carandina G, Mazzoni E et al. 2013. Age-specific seroprevalences of Merkel cell polyomavirus, human polyomaviruses 6, 7, and 9, and trichodysplasia spinulosa-associated polyomavirus. Clin. Vaccine Immunol. 20:363–68
    [Google Scholar]
  30. 30. 
    Martel-Jantin C, Pedergnana V, Nicol JT, Leblond V, Tregouet DA et al. 2013. Merkel cell polyomavirus infection occurs during early childhood and is transmitted between siblings. J. Clin. Virol. 58:288–91
    [Google Scholar]
  31. 31. 
    Tolstov YL, Pastrana DV, Feng H, Becker JC, Jenkins FJ et al. 2009. Human Merkel cell polyomavirus infection II. MCV is a common human infection that can be detected by conformational capsid epitope immunoassays. Int. J. Cancer 125:1250–56
    [Google Scholar]
  32. 32. 
    Kean JM, Rao S, Wang M, Garcea RL 2009. Seroepidemiology of human polyomaviruses. PLOS Pathog 5:e1000363
    [Google Scholar]
  33. 33. 
    Samimi M, Gardair C, Nicol JT, Arnold F, Touze A, Coursaget P 2015. Merkel cell polyomavirus in Merkel cell carcinoma: clinical and therapeutic perspectives. Semin. Oncol. 42:347–58
    [Google Scholar]
  34. 34. 
    Chang Y, Moore PS, Weiss RA 2017. Human oncogenic viruses: nature and discovery. Philos. Trans. R. Soc. B 372:20160264
    [Google Scholar]
  35. 35. 
    Rodig SJ, Cheng J, Wardzala J, DoRosario A, Scanlon JJ et al. 2012. Improved detection suggests all Merkel cell carcinomas harbor Merkel polyomavirus. J. Clin. Invest. 122:4645–53
    [Google Scholar]
  36. 36. 
    Schrama D, Peitsch WK, Zapatka M, Kneitz H, Houben R et al. 2011. Merkel cell polyomavirus status is not associated with clinical course of Merkel cell carcinoma. J. Invest. Dermatol. 131:1631–38
    [Google Scholar]
  37. 37. 
    Sihto H, Kukko H, Koljonen V, Sankila R, Bohling T, Joensuu H 2009. Clinical factors associated with Merkel cell polyomavirus infection in Merkel cell carcinoma. J. Natl. Cancer Inst. 101:938–45
    [Google Scholar]
  38. 38. 
    Sastre-Garau X, Peter M, Avril MF, Laude H, Couturier J et al. 2009. Merkel cell carcinoma of the skin: pathological and molecular evidence for a causative role of MCV in oncogenesis. J. Pathol. 218:48–56
    [Google Scholar]
  39. 39. 
    Handschel J, Muller D, Depprich RA, Ommerborn MA, Kubler NR et al. 2010. The new polyomavirus (MCPyV) does not affect the clinical course in MCCs. Int. J. Oral Maxillofac. Surg. 39:1086–90
    [Google Scholar]
  40. 40. 
    Harms PW, Vats P, Verhaegen ME, Robinson DR, Wu YM et al. 2015. The distinctive mutational spectra of polyomavirus-negative Merkel cell carcinoma. Cancer Res 75:3720–27
    [Google Scholar]
  41. 41. 
    Goh G, Walradt T, Markarov V, Blom A, Riaz N et al. 2016. Mutational landscape of MCPyV-positive and MCPyV-negative Merkel cell carcinomas with implications for immunotherapy. Oncotarget 7:3403–15
    [Google Scholar]
  42. 42. 
    Starrett GJ, Marcelus C, Cantalupo PG, Katz JP, Cheng J et al. 2017. Merkel cell polyomavirus exhibits dominant control of the tumor genome and transcriptome in virus-associated Merkel cell carcinoma. mBio 8:e02079-16
    [Google Scholar]
  43. 43. 
    Kassem A, Schopflin A, Diaz C, Weyers W, Stickeler E et al. 2008. Frequent detection of Merkel cell polyomavirus in human Merkel cell carcinomas and identification of a unique deletion in the VP1 gene. Cancer Res 68:5009–13
    [Google Scholar]
  44. 44. 
    Becker JC, Houben R, Ugurel S, Trefzer U, Pfohler C, Schrama D 2009. MC polyomavirus is frequently present in Merkel cell carcinoma of European patients. J. Invest. Dermatol. 129:248–50
    [Google Scholar]
  45. 45. 
    Busam KJ, Jungbluth AA, Rekthman N, Coit D, Pulitzer M et al. 2009. Merkel cell polyomavirus expression in Merkel cell carcinomas and its absence in combined tumors and pulmonary neuroendocrine carcinomas. Am. J. Surg. Pathol. 33:1378–85
    [Google Scholar]
  46. 46. 
    Garneski KM, Warcola AH, Feng Q, Kiviat NB, Leonard JH, Nghiem P 2009. Merkel cell polyomavirus is more frequently present in North American than Australian Merkel cell carcinoma tumors. J. Invest. Dermatol. 129:246–48
    [Google Scholar]
  47. 47. 
    Shuda M, Feng H, Kwun HJ, Rosen ST, Gjoerup O et al. 2008. T antigen mutations are a human tumor-specific signature for Merkel cell polyomavirus. PNAS 105:16272–77
    [Google Scholar]
  48. 48. 
    Diaz J, Wang X, Tsang SH, Jiao J, You J 2014. Phosphorylation of large T antigen regulates Merkel cell polyomavirus replication. Cancers 6:1464–86
    [Google Scholar]
  49. 49. 
    Houben R, Shuda M, Weinkam R, Schrama D, Feng H et al. 2010. Merkel cell polyomavirus-infected Merkel cell carcinoma cells require expression of viral T antigens. J. Virol. 84:7064–72
    [Google Scholar]
  50. 50. 
    Shuda M, Kwun HJ, Feng H, Chang Y, Moore PS 2011. Human Merkel cell polyomavirus small T antigen is an oncoprotein targeting the 4E-BP1 translation regulator. J. Clin. Invest. 121:3623–34
    [Google Scholar]
  51. 51. 
    Cheng J, Rozenblatt-Rosen O, Paulson KG, Nghiem P, DeCaprio JA 2013. Merkel cell polyomavirus large T antigen has growth-promoting and inhibitory activities. J. Virol. 87:6118–26
    [Google Scholar]
  52. 52. 
    Houben R, Adam C, Baeurle A, Hesbacher S, Grimm J et al. 2012. An intact retinoblastoma protein-binding site in Merkel cell polyomavirus large T antigen is required for promoting growth of Merkel cell carcinoma cells. Int. J. Cancer 130:847–56
    [Google Scholar]
  53. 53. 
    Sahi H, Savola S, Sihto H, Koljonen V, Bohling T, Knuutila S 2014. RB1 gene in Merkel cell carcinoma: hypermethylation in all tumors and concurrent heterozygous deletions in the polyomavirus-negative subgroup. APMIS 122:1157–66
    [Google Scholar]
  54. 54. 
    Cimino PJ, Robirds DH, Tripp SR, Pfeifer JD, Abel HJ, Duncavage EJ 2014. Retinoblastoma gene mutations detected by whole exome sequencing of Merkel cell carcinoma. Mod. Pathol. 27:1073–87
    [Google Scholar]
  55. 55. 
    Borchert S, Czech-Sioli M, Neumann F, Schmidt C, Wimmer P et al. 2014. High-affinity Rb binding, p53 inhibition, subcellular localization, and transformation by wild-type or tumor-derived shortened Merkel cell polyomavirus large T antigens. J. Virol. 88:3144–60
    [Google Scholar]
  56. 56. 
    Richards KF, Guastafierro A, Shuda M, Toptan T, Moore PS, Chang Y 2015. Merkel cell polyomavirus T antigens promote cell proliferation and inflammatory cytokine gene expression. J. Gen. Virol. 96:3532–44
    [Google Scholar]
  57. 57. 
    Hesbacher S, Pfitzer L, Wiedorfer K, Angermeyer S, Borst A et al. 2016. RB1 is the crucial target of the Merkel cell polyomavirus large T antigen in Merkel cell carcinoma cells. Oncotarget 7:32956–68
    [Google Scholar]
  58. 58. 
    Li J, Wang X, Diaz J, Tsang SH, Buck CB, You J 2013. Merkel cell polyomavirus large T antigen disrupts host genomic integrity and inhibits cellular proliferation. J. Virol. 87:9173–88
    [Google Scholar]
  59. 59. 
    Houben R, Dreher C, Angermeyer S, Borst A, Utikal J et al. 2013. Mechanisms of p53 restriction in Merkel cell carcinoma cells are independent of the Merkel cell polyoma virus T antigens. J. Invest. Dermatol. 133:2453–60
    [Google Scholar]
  60. 60. 
    Park DE, Cheng J, Berrios C, Montero J, Cortes-Cros M et al. 2019. Dual inhibition of MDM2 and MDM4 in virus-positive Merkel cell carcinoma enhances the p53 response. PNAS 116:1027–32
    [Google Scholar]
  61. 61. 
    Rodriguez-Viciana P, Collins C, Fried M 2006. Polyoma and SV40 proteins differentially regulate PP2A to activate distinct cellular signaling pathways involved in growth control. PNAS 103:19290–95
    [Google Scholar]
  62. 62. 
    Sontag E, Fedorov S, Kamibayashi C, Robbins D, Cobb M, Mumby M 1993. The interaction of SV40 small tumor antigen with protein phosphatase 2A stimulates the map kinase pathway and induces cell proliferation. Cell 75:887–97
    [Google Scholar]
  63. 63. 
    Kwun HJ, Shuda M, Camacho CJ, Gamper AM, Thant M et al. 2015. Restricted protein phosphatase 2A targeting by Merkel cell polyomavirus small T antigen. J. Virol. 89:4191–200
    [Google Scholar]
  64. 64. 
    Verhaegen ME, Mangelberger D, Harms PW, Vozheiko TD, Weick JW et al. 2015. Merkel cell polyomavirus small T antigen is oncogenic in transgenic mice. J. Invest. Dermatol. 135:1415–24
    [Google Scholar]
  65. 65. 
    Spurgeon ME, Cheng J, Bronson RT, Lambert PF, DeCaprio JA 2015. Tumorigenic activity of Merkel cell polyomavirus T antigens expressed in the stratified epithelium of mice. Cancer Res 75:1068–79
    [Google Scholar]
  66. 66. 
    Verhaegen ME, Mangelberger D, Harms PW, Eberl M, Wilbert DM et al. 2017. Merkel cell polyomavirus small T antigen initiates Merkel cell carcinoma-like tumor development in mice. Cancer Res 77:3151–57
    [Google Scholar]
  67. 67. 
    Shuda M, Guastafierro A, Geng X, Shuda Y, Ostrowski SM et al. 2015. Merkel cell polyomavirus small T antigen induces cancer and embryonic Merkel cell proliferation in a transgenic mouse model. PLOS ONE 10:e0142329
    [Google Scholar]
  68. 68. 
    Dye KN, Welcker M, Clurman BE, Roman A, Galloway DA 2019. Merkel cell polyomavirus tumor antigens expressed in Merkel cell carcinoma function independently of the ubiquitin ligases Fbw7 and beta-TrCP. PLOS Pathog 15:e1007543
    [Google Scholar]
  69. 69. 
    Kwun HJ, Shuda M, Feng H, Camacho CJ, Moore PS, Chang Y 2013. Merkel cell polyomavirus small T antigen controls viral replication and oncoprotein expression by targeting the cellular ubiquitin ligase SCFFbw7. Cell Host Microbe 14:125–35
    [Google Scholar]
  70. 70. 
    Berrios C, Padi M, Keibler MA, Park DE, Molla V et al. 2016. Merkel cell polyomavirus small T antigen promotes pro-glycolytic metabolic perturbations required for transformation. PLOS Pathog 12:e1006020
    [Google Scholar]
  71. 71. 
    Cheng J, Park DE, Berrios C, White EA, Arora R et al. 2017. Merkel cell polyomavirus recruits MYCL to the EP400 complex to promote oncogenesis. PLOS Pathog 13:e1006668
    [Google Scholar]
  72. 72. 
    Boulais N, Misery L. 2007. Merkel cells. J. Am. Acad. Dermatol. 57:147–65
    [Google Scholar]
  73. 73. 
    Merkel F. 1875. Tastzellen und Tastkörperchen bei den Hausthieren und beim Menschen. Arch. Mikrosk. Anat. 11:636–52
    [Google Scholar]
  74. 74. 
    Schowalter RM, Pastrana DV, Pumphrey KA, Moyer AL, Buck CB 2010. Merkel cell polyomavirus and two previously unknown polyomaviruses are chronically shed from human skin. Cell Host Microbe 7:509–15
    [Google Scholar]
  75. 75. 
    Pastrana DV, Tolstov YL, Becker JC, Moore PS, Chang Y, Buck CB 2009. Quantitation of human seroresponsiveness to Merkel cell polyomavirus. PLOS Pathog 5:e1000578
    [Google Scholar]
  76. 76. 
    Erickson KD, Garcea RL, Tsai B 2009. Ganglioside GT1b is a putative host cell receptor for the Merkel cell polyomavirus. J. Virol. 83:10275–79
    [Google Scholar]
  77. 77. 
    Neu U, Hengel H, Blaum BS, Schowalter RM, Macejak D et al. 2012. Structures of Merkel cell polyomavirus VP1 complexes define a sialic acid binding site required for infection. PLOS Pathog 8:e1002738
    [Google Scholar]
  78. 78. 
    Becker M, Dominguez M, Greune L, Soria-Martinez L, Pfleiderer MM et al. 2019. Infectious entry of Merkel cell polyomavirus. J. Virol. 93:e02004-18
    [Google Scholar]
  79. 79. 
    Neumann F, Borchert S, Schmidt C, Reimer R, Hohenberg H et al. 2011. Replication, gene expression and particle production by a consensus Merkel Cell Polyomavirus (MCPyV) genome. PLOS ONE 6:e29112
    [Google Scholar]
  80. 80. 
    Tsang SH, Wang X, Li J, Buck CB, You J 2014. Host DNA damage response factors localize to Merkel cell polyomavirus DNA replication sites to support efficient viral DNA replication. J. Virol. 88:3285–97
    [Google Scholar]
  81. 81. 
    Morrison KM, Miesegaes GR, Lumpkin EA, Maricich SM 2009. Mammalian Merkel cells are descended from the epidermal lineage. Dev. Biol. 336:76–83
    [Google Scholar]
  82. 82. 
    Calder KB, Smoller BR. 2010. New insights into Merkel cell carcinoma. Adv. Anat. Pathol. 17:155–61
    [Google Scholar]
  83. 83. 
    Vaigot P, Pisani A, Darmon YM, Ortonne JP 1987. The majority of epidermal Merkel cells are non-proliferative: a quantitative immunofluorescence analysis. Acta Derm. Venereol. 67:517–20
    [Google Scholar]
  84. 84. 
    Foulongne V, Sauvage V, Hebert C, Dereure O, Cheval J et al. 2012. Human skin microbiota: High diversity of DNA viruses identified on the human skin by high throughput sequencing. PLOS ONE 7:e38499
    [Google Scholar]
  85. 85. 
    Liu W, Yang R, Payne AS, Schowalter RM, Spurgeon ME et al. 2016. Identifying the target cells and mechanisms of Merkel cell polyomavirus infection. Cell Host Microbe 19:775–87
    [Google Scholar]
  86. 86. 
    Werner S, Grose R. 2003. Regulation of wound healing by growth factors and cytokines. Physiol. Rev. 83:835–70
    [Google Scholar]
  87. 87. 
    Chen D, Jarrell A, Guo C, Lang R, Atit R 2012. Dermal beta-catenin activity in response to epidermal Wnt ligands is required for fibroblast proliferation and hair follicle initiation. Development 139:1522–33
    [Google Scholar]
  88. 88. 
    Fisher GJ, Datta SC, Talwar HS, Wang ZQ, Varani J et al. 1996. Molecular basis of sun-induced premature skin ageing and retinoid antagonism. Nature 379:335–39
    [Google Scholar]
  89. 89. 
    Gill SE, Parks WC. 2008. Metalloproteinases and their inhibitors: regulators of wound healing. Int. J. Biochem. Cell Biol. 40:1334–47
    [Google Scholar]
  90. 90. 
    Cho S, Shin MH, Kim YK, Seo JE, Lee YM et al. 2009. Effects of infrared radiation and heat on human skin aging in vivo. J. Invest. Dermatol. Symp. Proc. 14:15–19
    [Google Scholar]
  91. 91. 
    Whyte JL, Smith AA, Helms JA 2012. Wnt signaling and injury repair. Cold Spring Harb. Perspect. Biol. 4:a008078
    [Google Scholar]
  92. 92. 
    Spurgeon ME, Lambert PF. 2013. Merkel cell polyomavirus: a newly discovered human virus with oncogenic potential. Virology 435:118–30
    [Google Scholar]
  93. 93. 
    Shuda M, Arora R, Kwun HJ, Feng H, Sarid R et al. 2009. Human Merkel cell polyomavirus infection I. MCV T antigen expression in Merkel cell carcinoma, lymphoid tissues and lymphoid tumors. Int. J. Cancer 125:1243–49
    [Google Scholar]
  94. 94. 
    Tang CK, Toker C. 1978. Trabecular carcinoma of the skin: an ultrastructural study. Cancer 42:2311–21
    [Google Scholar]
  95. 95. 
    Chan JK, Suster S, Wenig BM, Tsang WY, Chan JB, Lau AL 1997. Cytokeratin 20 immunoreactivity distinguishes Merkel cell (primary cutaneous neuroendocrine) carcinomas and salivary gland small cell carcinomas from small cell carcinomas of various sites. Am. J. Surg. Pathol. 21:226–34
    [Google Scholar]
  96. 96. 
    Scott MP, Helm KF. 1999. Cytokeratin 20: a marker for diagnosing Merkel cell carcinoma. Am. J. Dermatopathol. 21:16–20
    [Google Scholar]
  97. 97. 
    Zur Hausen A, Rennspiess D, Winnepenninckx V, Speel EJ, Kurz AK 2013. Early B-cell differentiation in Merkel cell carcinomas: clues to cellular ancestry. Cancer Res 73:4982–87
    [Google Scholar]
  98. 98. 
    Fan K, Gravemeyer J, Ritter C, Rasheed K, Gambichler T et al. 2020. MCPyV large T antigen-induced atonal homolog 1 is a lineage-dependency oncogene in Merkel cell carcinoma. J. Invest. Dermatol. 140:56–65
    [Google Scholar]
  99. 99. 
    Nemeth K, Gorog A, Mezey E, Pinter D, Kuroli E et al. 2016. Cover image: detection of hair follicle-associated Merkel cell polyomavirus in an immunocompromised host with follicular spicules and alopecia. Br. J. Dermatol. 175:1409
    [Google Scholar]
  100. 100. 
    Harold A, Amako Y, Hachisuka J, Bai Y, Li MY et al. 2019. Conversion of Sox2-dependent Merkel cell carcinoma to a differentiated neuron-like phenotype by T antigen inhibition. PNAS 116:20104–14
    [Google Scholar]
  101. 101. 
    Feng H, Kwun HJ, Liu X, Gjoerup O, Stolz DB et al. 2011. Cellular and viral factors regulating Merkel cell polyomavirus replication. PLOS ONE 6:e22468
    [Google Scholar]
  102. 102. 
    Wang X, Li J, Schowalter RM, Jiao J, Buck CB, You J 2012. Bromodomain protein Brd4 plays a key role in Merkel cell polyomavirus DNA replication. PLOS Pathog 8:e1003021
    [Google Scholar]
  103. 103. 
    Tsang SH, Wang R, Nakamaru-Ogiso E, Knight SA, Buck CB, You J 2016. The oncogenic small tumor antigen of Merkel cell polyomavirus is an iron-sulfur cluster protein that enhances viral DNA replication. J. Virol. 90:1544–56
    [Google Scholar]
  104. 104. 
    Shuda M, Chang Y, Moore PS 2014. Merkel cell polyomavirus-positive Merkel cell carcinoma requires viral small T-antigen for cell proliferation. J. Invest. Dermatol. 134:1479–81
    [Google Scholar]
  105. 105. 
    White MK, Safak M, Khalili K 2009. Regulation of gene expression in primate polyomaviruses. J. Virol. 83:10846–56
    [Google Scholar]
  106. 106. 
    Theiss JM, Gunther T, Alawi M, Neumann F, Tessmer U et al. 2015. A comprehensive analysis of replicating Merkel cell polyomavirus genomes delineates the viral transcription program and suggests a role for mcv-miR-M1 in episomal persistence. PLOS Pathog 11:e1004974
    [Google Scholar]
  107. 107. 
    Ajuh ET, Wu Z, Kraus E, Weissbach FH, Bethge T et al. 2018. Novel human polyomavirus noncoding control regions differ in bidirectional gene expression according to host cell, large T-antigen expression, and clinically occurring rearrangements. J. Virol. 92:e02231-17
    [Google Scholar]
  108. 108. 
    Liu W, Krump NA, MacDonald M, You J 2018. Merkel cell polyomavirus infection of animal dermal fibroblasts. J. Virol. 92:e01610-17
    [Google Scholar]
  109. 109. 
    Liu W, Krump NA, Buck CB, You J 2019. Merkel cell polyomavirus infection and detection. J. Vis. Exp. 2019:e58950
    [Google Scholar]
  110. 110. 
    Mogha A, Fautrel A, Mouchet N, Guo N, Corre S et al. 2010. Merkel cell polyomavirus small T antigen mRNA level is increased following in vivo UV-radiation. PLOS ONE 5:e11423
    [Google Scholar]
/content/journals/10.1146/annurev-virology-011720-121757
Loading
/content/journals/10.1146/annurev-virology-011720-121757
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error