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Journal of Virology, February 2006, p. 1922-1938, Vol. 80, No. 4
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.4.1922-1938.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Insights into Gene Expression Changes Impacting B-Cell Transformation: Cross-Species Microarray Analysis of Bovine Leukemia Virus Tax-Responsive Genes in Ovine B Cells

Pavel Klener,^1,2, Maud Szynal,^1, Yvette Cleuter,¹ Makram Merimi,¹ Hugues Duvillier,¹ Françoise Lallemand,¹ Claude Bagnis,³ Philip Griebel,⁴ Christos Sotiriou,¹ Arsène Burny,¹ Philippe Martiat,¹ and Anne Van den Broeke^1*

Laboratory of Experimental Hematology, Bordet Institute, 1000 Brussels, Belgium,¹ Institute of Pathological Physiology, Charles University, Prague, Czech Republic,² Etablissement Français du Sang, 13009 Marseille, France,³ Vaccine and Infectious Disease Organization, S7H5E3 Saskatoon, Canada⁴

Received 22 August 2005/ Accepted 18 November 2005

Large-animal models for leukemia have the potential to aid in the understanding of networks that contribute to oncogenesis. Infection of cattle and sheep with bovine leukemia virus (BLV), a complex retrovirus related to human T-cell leukemia virus type 1 (HTLV-1), is associated with the development of B-cell leukemia. Whereas the natural disease in cattle is characterized by a low tumor incidence, experimental infection of sheep leads to overt leukemia in the majority of infected animals, providing a model for studying the pathogenesis associated with BLV and HTLV-1. Tax_BLV, the major oncoprotein, initiates a cascade of events leading toward malignancy, although the basis of transformation is not fully understood. We have taken a cross-species ovine-to-human microarray approach to identify Tax_BLV-responsive transcriptional changes in two sets of cultured ovine B cells following retroviral vector-mediated delivery of Tax_BLV. Using cDNA-spotted microarrays comprising 10,336 human genes/expressed sequence tags, we identified a cohort of differentially expressed genes, including genes related to apoptosis, DNA transcription, and repair; proto-oncogenes; cell cycle regulators; transcription factors; small Rho GTPases/GTPase-binding proteins; and previously reported Tax_HTLV-1-responsive genes. Interestingly, genes known to be associated with human neoplasia, especially B-cell malignancies, were extensively represented. Others were novel or unexpected. The results suggest that Tax_BLV deregulates a broad network of interrelated pathways rather than a single B-lineage-specific regulatory process. Although cross-species approaches do not permit a comprehensive analysis of gene expression patterns, they can provide initial clues for the functional roles of genes that participate in B-cell transformation and pinpoint molecular targets not identified using other methods in animal models.

P.K. and M.S. contributed equally to this work.

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