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  • Original Paper
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Disruption of B-cell homeostatic control mediated by the BLV-Tax oncoprotein: association with the upregulation of Bcl-2 and signaling through NF-κB

Oncogene volume 22, pages 4531–4542 (2003)Cite this article

Abstract

Transactivating proteins associated with complex onco-retroviruses including human T-cell leukemia virus-1 (HTLV-1) and bovine leukemia virus (BLV) mediate transformation using poorly understood mechanisms. To gain insight into the processes that govern tumor onset and progression, we have examined the impact of BLV-Tax expression on ovine B-cells, the targets of BLV in experimentally infected sheep, using B-cell clones that are dependent on CD154 and γc-common cytokines. Tax was capable of mediating progression of B-cells from cytokine dependence to cytokine independence, indicating that the transactivator can over-ride signaling pathways typically controlled by cytokine receptor activation in B-cells. When examined in the presence of both CD154 and interleukin-4, Tax had a clear supportive role on B-cell growth, with an impact on B-cell proliferation, cell cycle phase distribution, and survival. Apoptotic B-cell death mediated by growth factor withdrawal, physical insult, and NF-κB inhibition was dramatically reduced in the presence of Tax. Furthermore, the expression of Tax was associated with higher Bcl-2 protein levels, providing rationale for the rescue signals mediated by the transactivator. Finally, Tax expression in B-cells led to a dramatic increase of nuclear RelB/p50 and p50/p50 NF-κB dimers, indicating that cellular signaling through NF-κB is a major contributory mechanism in the disruption of B-cell homeostasis. Although Tax is involved in aspects of pathogenesis that are unique to complex retroviruses, the viral strategies associated with this transactivating oncoprotein may have wide-ranging effects that are relevant to other B-cell malignancies.

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Acknowledgements

We thank Troy Randall for the generous gift of mCD154 L cells and Daniel Portetelle for providing the anti-Tax antibodies. This work was supported by funds from the F.N.R.S., the Fonds Medic, the Fondation Bekales, the G.V.P.N., the A.F.M., and the C.I.H.R. MS is supported by an F.R.I.A. F.N.R.S. grant and CVL is Maître de Recherches of the F.N.R.S.

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Authors and Affiliations

  1. Laboratory of Experimental Hematology, Bordet Institute, Brussels, 1000, Belgium

    Maud Szynal, Yvette Cleuter, Aisene Burny, Philippe Martiat & Anne Van den Broeke

  2. Veterinary Infectious Disease Organization, Saskatoon, S7H5E3, Canada

    Terry Beskorwayne & Philip Griebel

  3. Etablissement Français du Sang, Marseille, 13009, France

    Claude Bagnis

  4. IBMM, Gosselies, 6041, Belgium

    Carine Van Lint

  5. Coda-Cerva, Brussels, 1180, Belgium

    Pierre Kerkhofs

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Correspondence to Anne Van den Broeke.

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Szynal, M., Cleuter, Y., Beskorwayne, T. et al. Disruption of B-cell homeostatic control mediated by the BLV-Tax oncoprotein: association with the upregulation of Bcl-2 and signaling through NF-κB. Oncogene 22, 4531–4542 (2003). https://doi.org/10.1038/sj.onc.1206546

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