1. ¹Laboratory of Experimental Hematology, Bordet Institute, 1000 Brussels, Belgium
2. ²Veterinary Infectious Disease Organization, Saskatoon, Canada S7H5E3
3. ³Etablissement Français du Sang, 13009 Marseille, France
4. ⁴IBMM, 6041 Gosselies, Belgium
5. ⁵Coda-Cerva, 1180 Brussels, Belgium

Correspondence: A Van den Broeke, Laboratory of Experimental Hematology, Bordet Institute, 121, Blvd. De Waterloo, 1000 Brussels, Belgium. E-mail: anne_vandenbroeke@compuserve.com

Received 7 November 2002; Revised 3 March 2003; Accepted 3 March 2003.

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 _c-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-B 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-B dimers, indicating that cellular signaling through NF-B 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.