1932

Abstract

A third of soft tissue sarcomas have been shown to carry recurrent, characteristic chromosomal translocations, many of which generate fusion proteins that act as dominant transcription factors or as chromatin regulators. With routine use of massively parallel sequencing and advances in technology for the study of epigenetics and protein complexes, the last decade has seen a marked advancement in the identification of novel fusions and in our understanding of the mechanisms by which they contribute to the malignant state. Moreover, with new approaches in chemistry, such as the strategy of targeted protein degradation, we are now better poised to address these previously intractable targets. In this review, we describe three of the most common fusion-driven sarcomas (Ewing sarcoma, alveolar rhabdomyosarcoma, and synovial sarcoma), mechanistic themes emerging across these diseases, and novel approaches to their targeting.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-cancerbio-030518-055710
2019-03-04
2024-03-28
Loading full text...

Full text loading...

/deliver/fulltext/cancerbio/3/1/annurev-cancerbio-030518-055710.html?itemId=/content/journals/10.1146/annurev-cancerbio-030518-055710&mimeType=html&fmt=ahah

Literature Cited

  1. Alaggio R, Zhang L, Sung YS, Huang SC, Chen CL et al. 2016. A molecular study of pediatric spindle and sclerosing rhabdomyosarcoma: identification of novel and recurrent VGLL2-related fusions in infantile cases. Am. J. Surg. Pathol. 40:224–35
    [Google Scholar]
  2. Antonescu CR, Owosho AA, Zhang L, Chen S, Deniz K et al. 2017. Sarcomas with CIC-rearrangements are a distinct pathologic entity with aggressive outcome: a clinicopathologic and molecular study of 115 cases. Am. J. Surg. Pathol. 41:941–49
    [Google Scholar]
  3. Arnold MA, Barr FG 2017. Molecular diagnostics in the management of rhabdomyosarcoma. Expert Rev. Mol. Diagn. 17:189–94
    [Google Scholar]
  4. Banito A, Li X, Laporte AN, Roe JS, Sanchez-Vega F et al. 2018. The SS18-SSX oncoprotein hijacks KDM2B-PRC1.1 to drive synovial sarcoma. Cancer Cell 33:527–41.e8
    [Google Scholar]
  5. Barr FG, Chatten J, D'Cruz CM, Wilson AE, Nauta LE et al. 1995. Molecular assays for chromosomal translocations in the diagnosis of pediatric soft tissue sarcomas. JAMA 273:553–57
    [Google Scholar]
  6. Bennicelli JL, Advani S, Schafer BW, Barr FG 1999. PAX3 and PAX7 exhibit conserved cis-acting transcription repression domains and utilize a common gain of function mechanism in alveolar rhabdomyosarcoma. Oncogene 18:4348–56
    [Google Scholar]
  7. Bernt KM, Zhu N, Sinha AU, Vempati S, Faber J et al. 2011. MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L. Cancer Cell 20:66–78
    [Google Scholar]
  8. Bleloch JS, Ballim RD, Kimani S, Parkes J, Panieri E et al. 2017. Managing sarcoma: Where have we come from and where are we going. Ther. Adv. Med. Oncol. 9:637–59
    [Google Scholar]
  9. Bondeson DP, Crews CM 2017. Targeted protein degradation by small molecules. Annu. Rev. Pharmacol. Toxicol. 57:107–23
    [Google Scholar]
  10. Borkin D, He S, Miao H, Kempinska K, Pollock J et al. 2015. Pharmacologic inhibition of the Menin-MLL interaction blocks progression of MLL leukemia in vivo. Cancer Cell 27:589–602
    [Google Scholar]
  11. Boulay G, Sandoval GJ, Riggi N, Iyer S, Buisson R et al. 2017. Cancer-specific retargeting of BAF complexes by a prion-like domain. Cell 171:163–78.e19
    [Google Scholar]
  12. Bradner JE, Hnisz D, Young RA 2017. Transcriptional addiction in cancer. Cell 168:629–43
    [Google Scholar]
  13. Brohl AS, Solomon DA, Chang W, Wang J, Song Y et al. 2014. The genomic landscape of the Ewing Sarcoma family of tumors reveals recurrent STAG2 mutation. PLOS Genet 10:e1004475
    [Google Scholar]
  14. Buckley DL, Van Molle I, Gareiss PC, Tae HS, Michel J et al. 2012. Targeting the von Hippel–Lindau E3 ubiquitin ligase using small molecules to disrupt the VHL/HIF-1α interaction. J. Am. Chem. Soc. 134:4465–4465
    [Google Scholar]
  15. Budry L, Balsalobre A, Gauthier Y, Khetchoumian K, L'Honore A et al. 2012. The selector gene Pax7 dictates alternate pituitary cell fates through its pioneer action on chromatin remodeling. Genes Dev 26:2299–2299
    [Google Scholar]
  16. Cai W, Xiong Chen Z, Rane G, Satendra Singh S, Choo Z et al. 2017. Wanted DEAD/H or alive: helicases winding up in cancers. J. Natl. Cancer Inst. 109:djw278
    [Google Scholar]
  17. Cao L, Yu Y, Bilke S, Walker RL, Mayeenuddin LH et al. 2010. Genome-wide identification of PAX3-FKHR binding sites in rhabdomyosarcoma reveals candidate target genes important for development and cancer. Cancer Res 70:6497–508
    [Google Scholar]
  18. Carmody Soni EE, Schlottman S, Erkizan HV, Uren A, Toretsky JA 2014. Loss of SS18-SSX1 inhibits viability and induces apoptosis in synovial sarcoma. Clin. Orthop. Relat. Res. 472:874–82
    [Google Scholar]
  19. Chipumuro E, Marco E, Christensen CL, Kwiatkowski N, Zhang T et al. 2014. CDK7 inhibition suppresses super-enhancer-linked oncogenic transcription in MYCN-driven cancer. Cell 159:1126–39
    [Google Scholar]
  20. Clark J, Rocques PJ, Crew AJ, Gill S, Shipley J et al. 1994. Identification of novel genes, SYT and SSX, involved in the t(X;18)(p11.2;q11.2) translocation found in human synovial sarcoma. Nat. Genet. 7:502–8
    [Google Scholar]
  21. Coleman KG, Crews CM 2018. Proteolysis-targeting chimeras: harnessing the ubiquitin-proteasome system to induce degradation of specific target proteins. Annu. Rev. Cancer Biol. 2:41–58
    [Google Scholar]
  22. Coussens NP, Braisted JC, Peryea T, Sittampalam GS, Simeonov A, Hall MD 2017. Small-molecule screens: a gateway to cancer therapeutic agents with case studies of food and drug administration-approved drugs. Pharmacol. Rev. 69:479–96
    [Google Scholar]
  23. Couthouis J, Hart MP, Erion R, King OD, Diaz Z et al. 2012. Evaluating the role of the FUS/TLS-related gene EWSR1 in amyotrophic lateral sclerosis. Hum. Mol. Genet. 21:2899–911
    [Google Scholar]
  24. Couthouis J, Hart MP, Shorter J, DeJesus-Hernandez M, Erion R et al. 2011. A yeast functional screen predicts new candidate ALS disease genes. PNAS 108:20881–90
    [Google Scholar]
  25. Crompton BD, Stewart C, Taylor-Weiner A, Alexe G, Kurek KC et al. 2014. The genomic landscape of pediatric Ewing sarcoma. Cancer Discov 4:1326–41
    [Google Scholar]
  26. Crose LE, Galindo KA, Kephart JG, Chen C, Fitamant J et al. 2014. Alveolar rhabdomyosarcoma-associated PAX3-FOXO1 promotes tumorigenesis via Hippo pathway suppression. J. Clin. Investig. 124:285–96
    [Google Scholar]
  27. Davis RJ, Barr FG 1997. Fusion genes resulting from alternative chromosomal translocations are overexpressed by gene-specific mechanisms in alveolar rhabdomyosarcoma. PNAS 94:8047–51
    [Google Scholar]
  28. de Alava E. 2017. Ewing sarcoma, an update on molecular pathology with therapeutic implications. Surg. Pathol. Clin. 10:575–85
    [Google Scholar]
  29. de Leeuw B, Balemans M, Olde Weghuis D, Geurts van Kessel A 1995. Identification of two alternative fusion genes, SYT-SSX1 and SYT-SSX2, in t(X;18)(p11.2;q11.2)-positive synovial sarcomas. Hum. Mol. Genet. 4:1097–99
    [Google Scholar]
  30. Delattre O, Zucman J, Plougastel B, Desmaze C, Melot T et al. 1992. Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours. Nature 359:162–65
    [Google Scholar]
  31. Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J et al. 2011. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 146:904–17
    [Google Scholar]
  32. Demicco EG, Maki RG, Lev DC, Lazar AJ 2012. New therapeutic targets in soft tissue sarcoma. Adv. Anat. Pathol. 19:170–80
    [Google Scholar]
  33. Doebele RC, Davis LE, Vaishnavi A, Le AT, Estrada-Bernal A et al. 2015. An oncogenic NTRK fusion in a patient with soft-tissue sarcoma with response to the tropomyosin-related kinase inhibitor LOXO-101. Cancer Discov 5:1049–57
    [Google Scholar]
  34. Dos Santos GA, Kats L, Pandolfi PP 2013. Synergy against PML-RARa: targeting transcription, proteolysis, differentiation, and self-renewal in acute promyelocytic leukemia. J. Exp. Med. 210:2793–802
    [Google Scholar]
  35. Drilon A, Laetsch TW, Kummar S, DuBois SG, Lassen UN et al. 2018. Efficacy of larotrectinib in TRK fusion–positive cancers in adults and children. N. Engl. J. Med. 378:731–39
    [Google Scholar]
  36. Durbin AD, Zimmerman MW, Dharia NV, Abraham BJ, Balboni Iniguez A et al. 2018. Selective gene dependencies in MYCN-amplified neuroblastoma include the core transcriptional regulatory circuitry. Nat. Genet. 50:1240–46
    [Google Scholar]
  37. Esiashvili N, Goodman M, Marcus RB Jr. 2008. Changes in incidence and survival of Ewing sarcoma patients over the past 3 decades: Surveillance Epidemiology and End Results data. J. Pediatr. Hematol. Oncol. 30:425–30
    [Google Scholar]
  38. Fan Z, Yamaza T, Lee JS, Yu J, Wang S et al. 2009. BCOR regulates mesenchymal stem cell function by epigenetic mechanisms. Nat. Cell Biol. 11:1002–9
    [Google Scholar]
  39. Fredericks WJ, Galili N, Mukhopadhyay S, Rovera G, Bennicelli J et al. 1995. The PAX3-FKHR fusion protein created by the t(2;13) translocation in alveolar rhabdomyosarcomas is a more potent transcriptional activator than PAX3. Mol. Cell Biol. 15:1522–35
    [Google Scholar]
  40. Galili N, Davis RJ, Fredericks WJ, Mukhopadhyay S, Rauscher FJ 3rd et al. 1993. Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar rhabdomyosarcoma. Nat. Genet. 5:230–35
    [Google Scholar]
  41. Gangwal K, Sankar S, Hollenhorst PC, Kinsey M, Haroldsen SC et al. 2008. Microsatellites as EWS/FLI response elements in Ewing's sarcoma. PNAS 105:10149–54
    [Google Scholar]
  42. Gearhart MD, Corcoran CM, Wamstad JA, Bardwell VJ 2006. Polycomb group and SCF ubiquitin ligases are found in a novel BCOR complex that is recruited to BCL6 targets. Mol. Cell Biol. 26:6880–89
    [Google Scholar]
  43. Gechijian LN, Buckley DL, Lawlor MA, Reyes JM, Paulk J et al. 2018. Functional TRIM24 degrader via conjugation of ineffectual bromodomain and VHL ligands. Nat. Chem. Biol. 14:405–12
    [Google Scholar]
  44. Ginsberg JP, Davis RJ, Bennicelli JL, Nauta LE, Barr FG 1998. Up-regulation of MET but not neural cell adhesion molecule expression by the PAX3-FKHR fusion protein in alveolar rhabdomyosarcoma. Cancer Res 58:3542–46
    [Google Scholar]
  45. Gomez NC, Hepperla AJ, Dumitru R, Simon JM, Fang F, Davis IJ 2016. Widespread chromatin accessibility at repetitive elements links stem cells with human cancer. Cell Rep 17:1607–20
    [Google Scholar]
  46. Graham C, Chilton-MacNeill S, Zielenska M, Somers GR 2012. The CIC-DUX4 fusion transcript is present in a subgroup of pediatric primitive round cell sarcomas. Hum. Pathol. 43:180–89
    [Google Scholar]
  47. Grier HE, Krailo MD, Tarbell NJ, Link MP, Fryer CJ et al. 2003. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone. N. Engl. J. Med. 348:694–701
    [Google Scholar]
  48. Gryder BE, Yohe ME, Chou HC, Zhang X, Marques J et al. 2017. PAX3–FOXO1 establishes myogenic super enhancers and confers BET bromodomain vulnerability. Cancer Discov 7:884–99
    [Google Scholar]
  49. Guillon N, Tirode F, Boeva V, Zynovyev A, Barillot E, Delattre O 2009. The oncogenic EWS-FLI1 protein binds in vivo GGAA microsatellite sequences with potential transcriptional activation function. PLOS ONE 4:e4932
    [Google Scholar]
  50. Haldar M, Hancock JD, Coffin CM, Lessnick SL, Capecchi MR 2007. A conditional mouse model of synovial sarcoma: insights into a myogenic origin. Cancer Cell 11:375–88
    [Google Scholar]
  51. Hatta M, Cirillo LA 2007. Chromatin opening and stable perturbation of core histone:DNA contacts by FoxO1. J. Biol. Chem. 282:35583–93
    [Google Scholar]
  52. Hettmer S, Li Z, Billin AN, Barr FG, Cornelison DD et al. 2014. Rhabdomyosarcoma: current challenges and their implications for developing therapies. Cold Spring Harb. Perspect. Med. 4:a025650
    [Google Scholar]
  53. Huynh KD, Fischle W, Verdin E, Bardwell VJ 2000. BCoR, a novel corepressor involved in BCL-6 repression. Genes Dev 14:1810–23
    [Google Scholar]
  54. Italiano A, Sung YS, Zhang L, Singer S, Maki RG et al. 2012. High prevalence of CIC fusion with double-homeobox (DUX4) transcription factors in EWSR1-negative undifferentiated small blue round cell sarcomas. Genes Chromosomes Cancer 51:207–18
    [Google Scholar]
  55. Iwamoto Y. 2007. Diagnosis and treatment of Ewing's sarcoma. Jpn. J. Clin. Oncol. 37:79–89
    [Google Scholar]
  56. Joseph CG, Hwang H, Jiao Y, Wood LD, Kinde I et al. 2014. Exomic analysis of myxoid liposarcomas, synovial sarcomas, and osteosarcomas. Genes Chromosomes Cancer 53:15–24
    [Google Scholar]
  57. Kadoch C, Crabtree GR 2013. Reversible disruption of mSWI/SNF (BAF) complexes by the SS18-SSX oncogenic fusion in synovial sarcoma. Cell 153:71–85
    [Google Scholar]
  58. Kao YC, Owosho AA, Sung YS, Zhang L, Fujisawa Y et al. 2018. BCOR-CCNB3 fusion positive sarcomas: a clinicopathologic and molecular analysis of 36 cases with comparison to morphologic spectrum and clinical behavior of other round cell sarcomas. Am. J. Surg. Pathol. 42:604–15
    [Google Scholar]
  59. Kato M, Han TW, Xie S, Shi K, Du X et al. 2012. Cell-free formation of RNA granules: Low complexity sequence domains form dynamic fibers within hydrogels. Cell 149:753–67
    [Google Scholar]
  60. Kawamura-Saito M, Yamazaki Y, Kaneko K, Kawaguchi N, Kanda H et al. 2006. Fusion between CIC and DUX4 up-regulates PEA3 family genes in Ewing-like sarcomas with t(4;19)(q35;q13) translocation. Hum. Mol. Genet. 15:2125–37
    [Google Scholar]
  61. Keller C, Arenkiel BR, Coffin CM, El-Bardeesy N, DePinho RA, Capecchi MR 2004. Alveolar rhabdomyosarcomas in conditional Pax3:Fkhr mice: cooperativity of Ink4a/ARF and Trp53 loss of function. Genes Dev 18:2614–26
    [Google Scholar]
  62. Kobos R, Nagai M, Tsuda M, Merl MY, Saito T et al. 2013. Combining integrated genomics and functional genomics to dissect the biology of a cancer-associated, aberrant transcription factor, the ASPSCR1-TFE3 fusion oncoprotein. J. Pathol. 229:743–54
    [Google Scholar]
  63. Krönke J, Fink EC, Hollenbach PW, MacBeth KJ, Hurst SN et al. 2015. Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS. Nature 523:183–88
    [Google Scholar]
  64. Krönke J, Udeshi ND, Narla A, Grauman P, Hurst SN et al. 2014. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science 343:301–5
    [Google Scholar]
  65. Kwiatkowski N, Zhang T, Rahl PB, Abraham BJ, Reddy J et al. 2014. Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. Nature 511:616–20
    [Google Scholar]
  66. Kwon I, Kato M, Xiang S, Wu L, Theodoropoulos P et al. 2013. Phosphorylation-regulated binding of RNA polymerase II to fibrous polymers of low-complexity domains. Cell 155:1049–60
    [Google Scholar]
  67. Labropoulos SV, Razis ED 2007. Imatinib in the treatment of dermatofibrosarcoma protuberans. Biologics 1:347–53
    [Google Scholar]
  68. Ladanyi M, Lui MY, Antonescu CR, Krause-Boehm A, Meindl A et al. 2001. The der(17)t(X;17)(p11;q25) of human alveolar soft part sarcoma fuses the TFE3 transcription factor gene to ASPL, a novel gene at 17q25. Oncogene 20:48–57
    [Google Scholar]
  69. Laetsch TW, DuBois SG, Mascarenhas L, Turpin B, Federman N et al. 2018. Larotrectinib for paediatric solid tumours harbouring NTRK gene fusions: phase 1 results from a multicentre, open-label, phase 1/2 study. Lancet Oncol 19:705–14
    [Google Scholar]
  70. Larochelle S, Amat R, Glover-Cutter K, Sanso M, Zhang C et al. 2012. Cyclin-dependent kinase control of the initiation-to-elongation switch of RNA polymerase II. Nat. Struct. Mol. Biol. 19:1108–15
    [Google Scholar]
  71. Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K et al. 2013. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499:214–18
    [Google Scholar]
  72. Lessnick SL, Ladanyi M 2012. Molecular pathogenesis of Ewing sarcoma: new therapeutic and transcriptional targets. Annu. Rev. Pathol. 7:145–59
    [Google Scholar]
  73. Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM et al. 2013. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N. Engl. J. Med. 369:111–21
    [Google Scholar]
  74. Loupe JM, Miller PJ, Bonner BP, Maggi EC, Vijayaraghavan J et al. 2016. Comparative transcriptomic analysis reveals the oncogenic fusion protein PAX3-FOXO1 globally alters mRNA and miRNA to enhance myoblast invasion. Oncogenesis 5:e246
    [Google Scholar]
  75. Loven J, Hoke HA, Lin CY, Lau A, Orlando DA et al. 2013. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell 153:320–34
    [Google Scholar]
  76. Lu G, Middleton RE, Sun H, Naniong M, Ott CJ et al. 2014. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science 343:305–9
    [Google Scholar]
  77. Lu J, Qian Y, Altieri M, Dong H, Wang J et al. 2015. Hijacking the E3 ubiquitin ligase cereblon to efficiently target BRD4. Chem. Biol. 22:755–63
    [Google Scholar]
  78. Ma X, Wang J, Wang J, Ma CX, Gao X et al. 2017. The JAZF1-SUZ12 fusion protein disrupts PRC2 complexes and impairs chromatin repression during human endometrial stromal tumorogenesis. Oncotarget 8:4062–78
    [Google Scholar]
  79. March ZM, King OD, Shorter J 2016. Prion-like domains as epigenetic regulators, scaffolds for subcellular organization, and drivers of neurodegenerative disease. Brain Res 1647:9–18
    [Google Scholar]
  80. Mertens F, Johansson B, Fioretos T, Mitelman F 2015. The emerging complexity of gene fusions in cancer. Nat. Rev. Cancer 15:371–81
    [Google Scholar]
  81. McBride MJ, Kadoch C 2018. Disruption of mammalian SWI/SNF and polycomb complexes in human sarcomas: mechanisms and therapeutic opportunities. J. Pathol. 244:638–49
    [Google Scholar]
  82. McBride MJ, Pulice JL, Beird HC, Ingram DR, D'Avino AR et al. 2018. The SS18-SSX fusion oncoprotein hijacks BAF complex targeting and function to drive synovial sarcoma. Cancer Cell 33:1128–41
    [Google Scholar]
  83. Middeljans E, Wan X, Jansen PW, Sharma V, Stunnenberg HG, Logie C 2012. SS18 together with animal-specific factors defines human BAF-type SWI/SNF complexes. PLOS ONE 7:e33834
    [Google Scholar]
  84. Missiaglia E, Williamson D, Chisholm J, Wirapati P, Pierron G et al. 2012. PAX3/FOXO1 fusion gene status is the key prognostic molecular marker in rhabdomyosarcoma and significantly improves current risk stratification. J. Clin. Oncol. 30:1670–77
    [Google Scholar]
  85. Mosquera JM, Sboner A, Zhang L, Kitabayashi N, Chen CL et al. 2013. Recurrent NCOA2 gene rearrangements in congenital/infantile spindle cell rhabdomyosarcoma. Genes Chromosomes Cancer 52:538–50
    [Google Scholar]
  86. Nagai M, Tanaka S, Tsuda M, Endo S, Kato H et al. 2001. Analysis of transforming activity of human synovial sarcoma-associated chimeric protein SYT-SSX1 bound to chromatin remodeling factor hBRM/hSNF2α. PNAS 98:3843–48
    [Google Scholar]
  87. Ognjanovic S, Linabery AM, Charbonneau B, Ross JA 2009. Trends in childhood rhabdomyosarcoma incidence and survival in the United States, 1975–2005. Cancer 115:4218–26
    [Google Scholar]
  88. Owen DJ, Ornaghi P, Yang JC, Lowe N, Evans PR et al. 2000. The structural basis for the recognition of acetylated histone H4 by the bromodomain of histone acetyltransferase gcn5p. EMBO J 19:6141–6141
    [Google Scholar]
  89. Pandey PR, Chatterjee B, Olanich ME, Khan J, Miettinen MM et al. 2017. PAX3-FOXO1 is essential for tumour initiation and maintenance but not recurrence in a human myoblast model of rhabdomyosarcoma. J. Pathol. 241:626–37
    [Google Scholar]
  90. Parker BC, Zhang W 2013. Fusion genes in solid tumors: an emerging target for cancer diagnosis and treatment. Chin J. Cancer 32:594–603
    [Google Scholar]
  91. Peters TL, Kumar V, Polikepahad S, Lin FY, Sarabia SF et al. 2015. BCOR-CCNB3 fusions are frequent in undifferentiated sarcomas of male children. Mod Pathol 28:575–86
    [Google Scholar]
  92. Pierron G, Tirode F, Lucchesi C, Reynaud S, Ballet S et al. 2012. A new subtype of bone sarcoma defined by BCOR-CCNB3 gene fusion. Nat. Genet. 44:461–66
    [Google Scholar]
  93. Prieur A, Tirode F, Cohen P, Delattre O 2004. EWS/FLI-1 silencing and gene profiling of Ewing cells reveal downstream oncogenic pathways and a crucial role for repression of insulin-like growth factor binding protein 3. Mol. Cell Biol. 24:7275–83
    [Google Scholar]
  94. Riedel CG, Dowen RH, Lourenco GF, Kirienko NV, Heimbucher T et al. 2013. DAF-16 employs the chromatin remodeller SWI/SNF to promote stress resistance and longevity. Nat. Cell Biol. 15:491–501
    [Google Scholar]
  95. Riggi N, Knoechel B, Gillespie SM, Rheinbay E, Boulay G et al. 2014. EWS-FLI1 utilizes divergent chromatin remodeling mechanisms to directly activate or repress enhancer elements in Ewing sarcoma. Cancer Cell 26:668–81
    [Google Scholar]
  96. Sankar S, Bell R, Stephens B, Zhuo R, Sharma S et al. 2013. Mechanism and relevance of EWS/FLI-mediated transcriptional repression in Ewing sarcoma. Oncogene 32:5089–100
    [Google Scholar]
  97. Schmitt-Ney M, Camussi G 2015. The PAX3-FOXO1 fusion protein present in rhabdomyosarcoma interferes with normal FOXO activity and the TGF-β pathway. PLOS ONE 10:e0121474
    [Google Scholar]
  98. Schwartz JC, Wang X, Podell ER, Cech TR 2013. RNA seeds higher-order assembly of FUS protein. Cell Rep 5:918–25
    [Google Scholar]
  99. Shapiro DN, Sublett JE, Li B, Downing JR, Naeve CW 1993. Fusion of PAX3 to a member of the forkhead family of transcription factors in human alveolar rhabdomyosarcoma. Cancer Res 53:5108–12
    [Google Scholar]
  100. Sheffield NC, Pierron G, Klughammer J, Datlinger P, Schonegger A et al. 2017. DNA methylation heterogeneity defines a disease spectrum in Ewing sarcoma. Nat. Med. 23:386–95
    [Google Scholar]
  101. Shern JF, Chen L, Chmielecki J, Wei JS, Patidar R et al. 2014. Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors. Cancer Discov 4:216–31
    [Google Scholar]
  102. Skapek SX, Anderson J, Barr FG, Bridge JA, Gastier-Foster JM et al. 2013. PAX-FOXO1 fusion status drives unfavorable outcome for children with rhabdomyosarcoma: a children's oncology group report. Pediatr. Blood Cancer 60:1411–17
    [Google Scholar]
  103. Skytting B, Nilsson G, Brodin B, Xie Y, Lundeberg J et al. 1999. A novel fusion gene, SYT-SSX4, in synovial sarcoma. J. Natl. Cancer Inst. 91:974–75
    [Google Scholar]
  104. Soulez M, Saurin AJ, Freemont PS, Knight JC 1999. SSX and the synovial-sarcoma-specific chimaeric protein SYT-SSX co-localize with the human Polycomb group complex. Oncogene 18:2739–46
    [Google Scholar]
  105. Specht K, Sung YS, Zhang L, Richter GH, Fletcher CD, Antonescu CR 2014. Distinct transcriptional signature and immunoprofile of CIC-DUX4 fusion-positive round cell tumors compared to EWSR1-rearranged Ewing sarcomas: further evidence toward distinct pathologic entities. Genes Chromosomes Cancer 53:622–33
    [Google Scholar]
  106. Specht K, Zhang L, Sung YS, Nucci M, Dry S et al. 2016. Novel BCOR-MAML3 and ZC3H7B-BCOR gene fusions in undifferentiated small blue round cell sarcomas. Am. J. Surg. Pathol. 40:433–42
    [Google Scholar]
  107. Stein EM, Tallman MS 2015. Mixed lineage rearranged leukaemia: pathogenesis and targeting DOT1L. Curr. Opin. Hematol. 22:92–96
    [Google Scholar]
  108. Su L, Sampaio AV, Jones KB, Pacheco M, Goytain A et al. 2012. Deconstruction of the SS18-SSX fusion oncoprotein complex: insights into disease etiology and therapeutics. Cancer Cell 21:333–47
    [Google Scholar]
  109. Sultan I, Rodriguez-Galindo C, Saab R, Yasir S, Casanova M, Ferrari A 2009. Comparing children and adults with synovial sarcoma in the Surveillance, Epidemiology, and End Results program, 1983 to 2005: an analysis of 1268 patients. Cancer 115:3537–47
    [Google Scholar]
  110. Tamaki S, Fukuta M, Sekiguchi K, Jin Y, Nagata S et al. 2015. SS18-SSX, the oncogenic fusion protein in synovial sarcoma, is a cellular context-dependent epigenetic modifier. PLOS ONE 10:e0142991
    [Google Scholar]
  111. Tanaka K, Iwakuma T, Harimaya K, Sato H, Iwamoto Y 1997. EWS-Fli1 antisense oligodeoxynucleotide inhibits proliferation of human Ewing's sarcoma and primitive neuroectodermal tumor cells. J. Clin. Investig. 99:239–47
    [Google Scholar]
  112. Tang Y, Gholamin S, Schubert S, Willardson MI, Lee A et al. 2014. Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition. Nat. Med. 20:732–40
    [Google Scholar]
  113. Thaete C, Brett D, Monaghan P, Whitehouse S, Rennie G et al. 1999. Functional domains of the SYT and SYT-SSX synovial sarcoma translocation proteins and co-localization with the SNF protein BRM in the nucleus. Hum. Mol. Genet. 8:585–91
    [Google Scholar]
  114. Tirode F, Laud-Duval K, Prieur A, Delorme B, Charbord P, Delattre O 2007. Mesenchymal stem cell features of Ewing tumors. Cancer Cell 11:421–29
    [Google Scholar]
  115. Tirode F, Surdez D, Ma X, Parker M, Le Deley MC et al. 2014. Genomic landscape of Ewing sarcoma defines an aggressive subtype with co-association of STAG2 and TP53 mutations. Cancer Discov 4:1342–53
    [Google Scholar]
  116. Tomazou EM, Sheffield NC, Schmidl C, Schuster M, Schonegger A et al. 2015. Epigenome mapping reveals distinct modes of gene regulation and widespread enhancer reprogramming by the oncogenic fusion protein EWS-FLI1. Cell Rep 10:1082–95
    [Google Scholar]
  117. Toure M, Crews CM 2016. Small-molecule PROTACS: new approaches to protein degradation. Angew. Chem. Int. Ed. 55:1966–73
    [Google Scholar]
  118. Turc-Carel C, Philip I, Berger MP, Philip T, Lenoir GM 1984. Chromosome study of Ewing's sarcoma (ES) cell lines: consistency of a reciprocal translocation t(11;22)(q24;q12). Cancer Genet. Cytogenet 12:1–19
    [Google Scholar]
  119. Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F et al. 2004. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 303:844–48
    [Google Scholar]
  120. Vlenterie M, Hillebrandt-Roeffen MHS, Flucke UE, Groenen PJTA, Tops BBJ et al. 2015. Next generation sequencing in synovial sarcoma reveals novel gene mutations. Oncotarget 6:34680–90
    [Google Scholar]
  121. von Levetzow C, Jiang X, Gwye Y, von Levetzow G, Hung L et al. 2011. Modeling initiation of Ewing sarcoma in human neural crest cells. PLOS ONE 6:e19305
    [Google Scholar]
  122. Walters ZS, Villarejo-Balcells B, Olmos D, Buist TW, Missiaglia E et al. 2014. JARID2 is a direct target of the PAX3-FOXO1 fusion protein and inhibits myogenic differentiation of rhabdomyosarcoma cells. Oncogene 33:1148–57
    [Google Scholar]
  123. Wang S, Song R, Sun T, Hou B, Hong G et al. 2017. Survival changes in patients with synovial sarcoma, 1983–2012. J. Cancer 8:1759–68
    [Google Scholar]
  124. Whyte WA, Orlando DA, Hnisz D, Abraham BJ, Lin CY et al. 2013. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell 153:307–19
    [Google Scholar]
  125. Winter GE, Buckley DL, Paulk J, Roberts JM, Souza A et al. 2015. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science 348:1376–81
    [Google Scholar]
  126. Yokoyama A, Somervaille TC, Smith KS, Rozenblatt-Rosen O, Meyerson M, Cleary ML 2005. The menin tumor suppressor protein is an essential oncogenic cofactor for MLL-associated leukemogenesis. Cell 123:207–18
    [Google Scholar]
  127. Yoshimoto T, Tanaka M, Homme M, Yamazaki Y, Takazawa Y et al. 2017. CIC-DUX4 induces small round cell sarcomas distinct from Ewing sarcoma. Cancer Res 77:2927–37
    [Google Scholar]
  128. Zeng L, Zhou MM 2002. Bromodomain: an acetyl-lysine binding domain. FEBS Lett 513:124–28
    [Google Scholar]
/content/journals/10.1146/annurev-cancerbio-030518-055710
Loading
/content/journals/10.1146/annurev-cancerbio-030518-055710
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