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Journal of Virology, July 2009, p. 6909-6916, Vol. 83, No. 13
0022-538X/09/$08.00+0     doi:10.1128/JVI.00216-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Downregulation of RUNX1 by RUNX3 Requires the RUNX3 VWRPY Sequence and Is Essential for Epstein-Barr Virus-Driven B-Cell Proliferation{triangledown}

Gareth Brady, Hannah J. Whiteman,{dagger} Lindsay C. Spender,{ddagger} and Paul J. Farrell*

Department of Virology, Faculty of Medicine, Imperial College London, Norfolk Place, London W2 1PG, United Kingdom

Received 30 January 2009/ Accepted 22 April 2009

Cross-regulation of RUNX1 expression by RUNX3 plays a critical role in regulating proliferation of human B cells infected with Epstein-Barr virus (EBV). When EBV infection induces RUNX3, the consequent reduction in RUNX1 levels is required for the ensuing cell proliferation because forced expression of RUNX1 in an EBV lymphoblastoid cell line prevented cell proliferation. The TEL-RUNX1 fusion gene from acute B-lymphocytic leukemia retains almost all of the RUNX1 sequence but does not prevent B-cell proliferation in the same assay. B-cell maturation antigen (BCMA) was found to be induced by conditionally expressed RUNX3 in a lymphoma cell line. Chromatin immunoprecipitation assays confirmed that RUNX3 binds to the RUNX1 promoter in a lymphoblastoid cell line and a Burkitt's lymphoma cell line. The TLE binding VWRPY sequence from the C terminus of RUNX3 was found to be required for repression of the RUNX1 P1 promoter in a B-lymphoma cell line. The mechanism of repression in B-cell lines most likely involves recruitment of corepressor TLE3 or TLE4 to the RUNX1 promoter. The results demonstrate the importance of RUNX3-mediated repression of RUNX1 for EBV-driven B-cell proliferation and identify functional differences between human RUNX family proteins.

* Corresponding author. Mailing address: Department of Virology, Faculty of Medicine, Imperial College London, Norfolk Place, London W2 1PG, United Kingdom. Phone: 44 20 7594 2005. Fax: 44 20 7594 3973. E-mail: p.farrell{at}imperial.ac.uk

{triangledown} Published ahead of print on 29 April 2009.

{dagger} Present address: Cancer Research UK, 61 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom.

{ddagger} Present address: Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, United Kingdom.

Journal of Virology, July 2009, p. 6909-6916, Vol. 83, No. 13
0022-538X/09/$08.00+0     doi:10.1128/JVI.00216-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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