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Gene fusions involving PAX and FOX family members in alveolar rhabdomyosarcoma

Abstract

The chromosomal translocations t(2;13)(q35;q14) and t(1;13)(p36;q14) are characteristic of alveolar rhabdomyosarcoma, a pediatric soft tissue cancer related to the striated muscle lineage. These translocations rearrange PAX3 and PAX7, members of the paired box transcription factor family, and juxtapose these genes with FKHR, a member of the fork head transcription factor family. This juxtaposition generates PAX3–FKHR and PAX7–FKHR chimeric genes that are expressed as chimeric transcripts that encode chimeric proteins. The fusion proteins, which contain the PAX3/PAX7 DNA binding domain and the FKHR transcriptional activation domain, activate transcription from PAX-binding sites with higher potency than the corresponding wild-type PAX proteins. This increased function results from the insensitivity of the FKHR activation domain to inhibitory effects of N-terminal PAX3/PAX7 domains. In addition to altered function, the fusion products are expressed in ARMS tumors at higher levels than the corresponding wild-type PAX products due to two distinct mechanisms. The PAX7–FKHR fusion is overexpressed as a result of in vivo amplification while the PAX3–FKHR fusion is overexpressed due to a copy number-independent increase in transcriptional rate. Finally, though FKHR subcellular localization is regulated by an AKT-dependent pathway, the fusion proteins are resistant to these signals and show exclusively nuclear localization. Therefore, these translocations alter biological activity at the levels of protein function, gene expression, and subcellular localization with the cumulative outcome postulated to be aberrant regulation of PAX3/PAX7 target genes. This aberrant gene expression program is then hypothesized to contribute to tumorigenic behavior by impacting on the control of growth, apoptosis, differentiation and motility.

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References

  • Anderson MJ, Shelton GD, Cavenee WK, Arden KC . 2001 Proc. Natl. Acad. Sci. USA 98: 1589–1594

  • Anderson MJ, Viars CS, Czekay S, Cavenee WK, Arden KC . 1998 Genomics 47: 187–199

  • Arden KC, Anderson MJ, Finckenstein FG, Czekay S, Cavenee WK . 1996 Genes Chrom. Cancer 16: 254–260

  • Ayyanathan K, Fredericks WJ, Berking C, Herlyn M, Balakrishnan C, Gunther E, Rauscher III FJ . 2000 Cancer Res. 60: 5803–5814

  • Baldwin CT, Hoth CF, Amos JA, da-Silva EO, Milunsky A . 1992 Nature 355: 637–638

  • Barr FG, Chatten J, D'Cruz CM, Wilson AE, Nauta LE, Nycum LM, Biegel JA, Womer RB . 1995 JAMA 273: 553–557

  • Barr FG, Fitzgerald JC, Ginsberg JP, Vanella ML, Davis RJ, Bennicelli JL . 1999 Cancer Res. 59: 5443–5448

  • Barr FG, Galili N, Holick J, Biegel JA, Rovera G, Emanuel BS . 1993 Nat. Genet. 3: 113–117

  • Barr FG, Nauta LE, Davis RJ, Schafer BW, Nycum LM, Biegel JA . 1996 Hum Mol. Genet. 5: 15–21

  • Barr FG, Nauta LE, Hollows JC . 1998 Cancer Genet. Cytogenet. 102: 32–39

  • Bendall AJ, Ding J, Hu G, Shen MM, Abate-Shen C . 1999 Development 126: 4965–4976

  • Bennicelli JL, Advani S, Schafer BW, Barr FG . 1999 Oncogene 18: 4348–4356

  • Bennicelli JL, Edwards RH, Barr FG . 1996 Proc. Natl. Acad. Sci. USA 93: 5455–5459

  • Bennicelli JL, Fredericks WJ, Wilson RB, Rauscher FJ, Barr FG . 1995 Oncogene 11: 119–130

  • Bernasconi M, Remppis A, Fredericks WJ, Rauscher FJ, Schafer BW . 1996 Proc. Natl. Acad. Sci. USA 93: 13164–13169

  • Biegel JA, Meek RS, Parmiter AH, Conard K, Emanuel BS . 1991 Genes Chrom. Cancer 3: 483–484

  • Bladt F, Riethmacher D, Isenmann S, Aguzzi A, Birchmeier C . 1995 Nature 376: 768–771

  • Bober E, Franz T, Arnold HH, Gruss P, Tremblay P . 1994 Development 120: 603–612

  • Borkhardt A, Repp R, Haas OA, Leis T, Harbott J, Kreuder J, Hammermann J, Henn T, Lampert F . 1997 Oncogene 14: 195–202

  • Borycki AG, Li J, Jin F, Emerson CP, Epstein JA . 1999 Development 126: 1665–1674

  • Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME . 1999 Cell 96: 857–868

  • Burri M, Tromvoukis Y, Bopp D, Frigerio G, Noll M . 1989 EMBO J. 8: 1183–1190

  • Cao Y, Wang C . 2000 J. Biol. Chem. 275: 9854–9862

  • Chalepakis G, Goulding M, Read A, Strachan T, Gruss P . 1994a Proc. Natl. Acad. Sci. USA 91: 3685–3689

  • Chalepakis G, Gruss P . 1995 Gene 162: 267–270

  • Chalepakis G, Jones FS, Edelman GM, Gruss P . 1994b Proc. Natl. Acad. Sci. USA 91: 12745–12749

  • Czerny T, Schaffner G, Busslinger M . 1993 Genes Dev. 7: 2048–2061

  • Dahl E, Koseki H, Balling R . 1997 Bioessays 19: 755–765

  • Daston G, Lamar E, Olivier M, Goulding M . 1996 Development 122: 1017–1027

  • Davis RJ, Barr FG . 1997 Proc. Natl. Acad. Sci. USA 94: 8047–8051

  • Davis RJ, Bennicelli JL, Macina RA, Nycum LM, Biegel JA, Barr FG . 1995 Hum Mol. Genet. 4: 2355–2362

  • Davis RJ, D'Cruz CM, Lovell MA, Biegel JA, Barr FG . 1994 Cancer Res. 54: 2869–2872

  • de Alava E, Ladanyi M, Rosai J, Gerald WL . 1995 Am. J. Pathol. 147: 1584–1591

  • del Peso L, Gonzalez VM, Hernandez R, Barr FG, Nunez G . 1999 Oncogene 18: 7328–7333

  • Douglass EC, Rowe ST, Valentine M, Parham DM, Berkow R, Bowman WP, Maurer HM . 1991 Genes Chrom. Cancer 3: 480–482

  • Douglass EC, Valentine M, Etcubanas E, Parham D, Webber BL, Houghton PJ, Houghton JA, Green AA . 1987 Cytogenet. Cell Genet. 45: 148–155

  • Downing JR, Khandekar A, Shurtleff SA, Head DR, Parham DM, Webber BL, Pappo AS, Hulshof MG, Conn WP, Shapiro DN . 1995 Am. J. Pathol. 146: 626–634

  • Epstein DJ, Vekemans M, Gros P . 1991 Cell 67: 767–774

  • Epstein JA, Lam P, Jepeal L, Maas RL, Shapiro DN . 1995 J. Biol. Chem. 270: 11719–11722

  • Epstein JA, Shapiro DN, Cheng J, Lam PY, Maas RL . 1996 Proc. Natl. Acad. Sci. USA 93: 4213–4218

  • Epstein JA, Song B, Lakkis M, Wang C . 1998 Mol. Cell. Biol. 18: 4118–4130

  • Fitzgerald JC, Scherr AM, Barr FG . 2000 Cancer Genet. Cytogenet. 117: 37–40

  • Fortin AS, Underhill DA, Gros P . 1997 Hum. Mol. Genet. 6: 1781–1790

  • Franz T, Kothary R, Surani MA, Halata Z, Grim M . 1993 Anat. Embryol. 187: 153–160

  • Frascella E, Toffolatti L, Rosolen A . 1998 Cancer Genet. Cytogenet. 102: 104–109

  • Fredericks WJ, Ayyanathan K, Herlyn M, Friedman JR, Rauscher FJ III . 2000 Mol. Cell. Biol. 20: 5019–5031

  • Fredericks WJ, Galili N, Mukhopadhyay S, Rovera G, Bennicelli J, Barr FG, Rauscher FJ . 1995 Mol. Cell. Biol. 15: 1522–1535

  • Furuyama T, Nakazawa T, Nakano I, Mori N . 2000 Biochem. J. 349: 629–634

  • Galibert MD, Yavuzer U, Dexter TJ, Goding CR . 1999 J. Biol. Chem. 274: 26894–26900

  • Galili N, Davis RJ, Fredericks WJ, Mukhopadhyay S, Rauscher FJ, Emanuel BS, Rovera G, Barr FG . 1993 Nat. Genet. 5: 230–235

  • Goulding M, Lumsden A, Paquette AJ . 1994 Development 120: 957–971

  • Goulding MD, Chalepakis G, Deutsch U, Erselius JR, Gruss P . 1991 EMBO J. 10: 1135–1147

  • Guo S, Rena G, Cichy S, He X, Cohen P, Unterman T . 1999 J. Biol. Chem. 274: 17184–17192

  • Henderson DJ, Ybot-Gonzalez P, Copp AJ . 1997 Mech. Dev. 69: 39–51

  • Hillion J, Le Coniat M, Jonveaux P, Berger R, Bernard OA . 1997 Blood 90: 3714–3719

  • Hollenbach AD, Sublett JE, McPherson CJ, Grosveld G . 1999 EMBO J. 18: 3702–3711

  • Jostes B, Walther C, Gruss P . 1990 Mech. Dev. 33: 27–37

  • Kaestner KH, Knochel W, Martinez DE . 2000 Genes Dev. 14: 142–146

  • Kallunki P, Jenkinson S, Edelman GM, Jones FS . 1995 J. Biol. Chem. 270: 21291–21298

  • Kaufmann E, Knochel W . 1996 Mech. Dev. 57: 3–20

  • Kelly KM, Womer RB, Sorensen PH, Xiong QB, Barr FG . 1997 J. Clin. Oncol. 15: 1831–1836

  • Khan J, Simon R, Bittner M, Chen Y, Leighton SB, Pohida T, Smith PD, Jiang Y, Gooden GC, Trent JM, Meltzer PS . 1998 Cancer Res. 58: 5009–5013

  • Lagutina I, Sublett J, McPherson C, Conway S, Grosveld G . 2000 Dev. Biol. 222: 236

  • Lam PY, Sublett JE, Hollenbach AD, Roussel MF . 1999 Mol. Cell. Biol. 19: 594–601

  • Lang D, Chen F, Milewski R, Li J, Lu MM, Epstein JA . 2000 J. Clin. Invest. 106: 963–971

  • Lin K, Dorman JB, Rodan A, Kenyon C . 1997 Science 278: 1319–1322

  • Macina RA, Barr FG, Galili N, Riethman HC . 1995 Genomics 26: 1–8

  • Mackall C, Berzofsky J, Helman LJ . 2000 Clin. Orthop. 373: 25–31

  • Magnaghi P, Roberts C, Lorain S, Lipinski M, Scambler PJ . 1998 Nat. Genet. 20: 74–77

  • Mansouri A, Stoykova A, Torres M, Gruss P . 1996 Development 122: 831–838

  • Margue CM, Bernasconi M, Barr FG, Schafer BW . 2000 Oncogene 19: 2921–2929

  • Maroto M, Reshef R, Munsterberg AE, Koester S, Goulding M, Lassar AB . 1997 Cell 89: 139–148

  • Massuda ES, Dunphy EJ, Redman RA, Schreiber JJ, Nauta LE, Barr FG, Maxwell IH, Cripe TP . 1997 Proc. Natl. Acad. Sci. USA 94: 14701–14706

  • Medema RH, Kops GJ, Bos JL, Burgering BM . 2000 Nature 404: 782–787

  • Mennerich D, Schafer K, Braun T . 1998 Mech. Dev. 73: 147–158

  • Ogg S, Paradis S, Gottlieb S, Patterson GI, Lee L, Tissenbaum HA, Ruvkun G . 1997 Nature 389: 994–999

  • Phelan SA, Loeken MR . 1998 J. Biol. Chem. 273: 19153–19159

  • Reichmuth C, Markus MA, Hillemanns M, Atkinson MJ, Unni KK, Saretzki G, Hofler H . 1996 J. Pathol. 180: 50–57

  • Schafer BW, Czerny T, Bernasconi M, Genini M, Busslinger M . 1994 Nucleic Acids Res. 22: 4574–4582

  • Scheidler S, Fredericks WJ, Rauscher FJ, Barr FG, Vogt PK . 1996 Proc. Natl. Acad. Sci. USA 93: 9805–9809

  • Seale P, Sabourin LA, Girgis-Gabardo A, Mansouri A, Gruss P, Rudnicki MA . 2000 Cell 102: 777–786

  • Shapiro DN, Sublett JE, Li B, Downing JR, Naeve CW . 1993 Cancer Res. 53: 5108–5112

  • Sublett JE, Jeon IS, Shapiro DN . 1995 Oncogene 11: 545–552

  • Tajbakhsh S, Rocancourt D, Cossu G, Buckingham M . 1997 Cell 89: 127–138

  • Takaishi H, Konishi H, Matsuzaki H, Ono Y, Shirai Y, Saito N, Kitamura T, Ogawa W, Kasuga M, Kikkawa U, Nishizuka Y . 1999 Proc. Natl. Acad. Sci. USA 96: 11836–11841

  • Tang ED, Nunez G, Barr FG, Guan KL . 1999 J. Biol. Chem. 274: 16741–16746

  • Tassabehji M, Read AP, Newton VE, Harris R, Balling R, Gruss P, Strachan T . 1992 Nature 355: 635–636

  • Toretsky JA, Helman LJ . 1996 J. Endocrinol. 149: 367–372

  • Treisman J, Harris E, Desplan C . 1991 Genes Dev. 5: 594–604

  • Tremblay P, Gruss P . 1994 Pharmacol. Ther. 61: 205–226

  • Tsokos M . 1994 Semin. Diagn. Pathol. 11: 26–38

  • Tsokos M, Webber BL, Parham DM, Wesley RA, Miser A, Miser JS, Etcubanas E, Kinsella T, Grayson J, Glatstein E, Pizzo P, Triche TJ . 1992 Arch. Pathol. Lab. Med. 116: 847–855

  • Turc-Carel C, Lizard-Nacol S, Justrabo E, Favrot M, Philip T, Tabone E . 1986 Cancer Genet. Cytogenet. 19: 361–362

  • Underhill DA, Gros P . 1997 J. Biol. Chem. 272: 14175–14182

  • Underhill DA, Vogan KJ, Gros P . 1995 Proc. Natl. Acad. Sci. USA 92: 3692–3696

  • Vogan KJ, Underhill DA, Gros P . 1996 Mol. Cell. Biol. 16: 6677–6686

  • Vorobyov E, Mertsalov I, Dockhorn-Dworniczak B, Dworniczak B, Horst J . 1997 Genomics 45: 168–174

  • Wang-Wuu S, Soukup S, Ballard E, Gotwals B, Lampkin B . 1988 Cancer Res. 48: 983–987

  • Watanabe A, Takeda K, Ploplis B, Tachibana M . 1998 Nat. Genet. 18: 283–286

  • Wexler LH, Helman LJ . (1997). Principles and Practices of Pediatric Oncology Pizzo PA and Poplack DG. (eds) Lippincott-Raven: Philadelphia pp. 799–829

    Google Scholar 

  • Wiggan O, Taniguchi-Sidle A, Hamel PA . 1998 Oncogene 16: 227–236

  • Williams BA, Ordahl CP . 1994 Development 120: 785–796

  • Xie E, Zhu Q, Barr F, Robinson M, Sferra T, Muthusamy R, Qualman S, Durbin J . 2001 Mod. Pathol. 14: 4P

  • Yang XM, Vogan K, Gros P, Park M . 1996 Development 122: 2163–2171

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Acknowledgements

This work was supported in part by NIH grants CA64202, CA71838 and CA89461.

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Correspondence to Frederic G Barr.

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Barr, F. Gene fusions involving PAX and FOX family members in alveolar rhabdomyosarcoma. Oncogene 20, 5736–5746 (2001). https://doi.org/10.1038/sj.onc.1204599

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