The Journal of Experimental Medicine
Janeway's Immunobiology 7th Edition
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Published online 14 November 2005 doi:10.1084/jem.20050730
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 202, Number 10, 1399-1410
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ARTICLE

 Coordinated oncogenic transformation and inhibition of host immune responses by the PAX3-FKHR fusion oncoprotein

Stephen Nabarro1, Nourredine Himoudi1, Antigoni Papanastasiou1, Kimberly Gilmour2, Sian Gibson3, Neil Sebire3, Adrian Thrasher2, Michael P. Blundell2, Mike Hubank1, Glenda Canderan1, and John Anderson1

1 Unit of Molecular Haematology and Cancer Biology, Institute of Child Health, London WC1N 1EH, England, UK
2 Unit of Molecular Immunology, Institute of Child Health, London WC1N 1EH, England, UK
3 Department of Histopathology, Great Ormond Street Hospital for Children, London WC1N 3JH, England, UK

CORRESPONDENCE John Anderson: j.anderson{at}ich.ucl.ac.uk

Tumors have evolved elaborate mechanisms for evading immune detection, such as production of immunoinhibitory cytokines and down-regulation of major histocompatibility complex (MHC) expression. We have studied PAX3-FKHR as an example of an oncogenic fusion protein associated with an aggressive metastatic cancer. We show that PAX3-FKHR alters expression of genes that are normally regulated by Janus kinase/signal transducer and activator of transcription (STAT) signaling pathways. This occurs as a result of a specific interaction between PAX3-FKHR and the STAT3 transcription factor, which results in a dramatic reduction in tumor MHC expression, and an alteration in local cytokine concentrations to inhibit surrounding inflammatory cells and immune detection. Collectively, these data show that an oncogenic transcription factor can promote tumor growth and tissue invasion while inhibiting local inflammatory and immune responses. This is the first time that an immunomodulatory role has been described for an oncogenic fusion protein.

Abbreviations used: CM, conditioned medium; 4HT, 4-hydroxy-tamoxifen; RMS, rhabdomyosarcoma; siRNA, small interfering RNA; TAP, transporter associated with antigen processing.

S. Nabarro, N. Himoudi, and A. Papanastasiou contributed equally to this work.


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