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Chemoresistance to Valproate Treatment of Bovine Leukemia Virus-Infected Sheep; Identification of Improved HDAC Inhibitors
Molecular and Cellular Epigenetics (GIGA) and Molecular Biology (GxABT), University of Liège, Liège 4000, Belgium
Pharmaceutic Chemistry and Radiopharmacy Unit, Louvain Drug Research Institute, University of Louvain, Brussels 1000, Belgium
Biological Chemistry, Facultés Universitaires Notre-Dame de la Paix, Namur 5000, Belgium
* Author to whom correspondence should be addressed.
Received: 5 September 2012; in revised form: 24 September 2012 / Accepted: 2 October 2012 / Published: 8 October 2012
Abstract: We previously proved that a histone deacetylase inhibitor (valproate, VPA) decreases the number of leukemic cells in bovine leukemia virus (BLV)-infected sheep. Here, we characterize the mechanisms initiated upon interruption of treatment. We observed that VPA treatment is followed by a decrease of the B cell counts and proviral loads (copies per blood volume). However, all sheep eventually relapsed after different periods of time and became refractory to further VPA treatment. Sheep remained persistently infected with BLV. B lymphocytes isolated throughout treatment and relapse were responsive to VPA-induced apoptosis in cell culture. B cell proliferation is only marginally affected by VPA ex vivo. Interestingly, in four out of five sheep, ex vivo viral expression was nearly undetectable at the time of relapse. In two sheep, a new tumoral clone arose, most likely revealing a selection process exerted by VPA in vivo. We conclude that the interruption of VPA treatment leads to the resurgence of the leukemia in BLV-infected sheep and hypothesize that resistance to further treatment might be due to the failure of viral expression induction. The development of more potent HDAC inhibitors and/or the combination with other compounds can overcome chemoresistance. These observations in the BLV model may be important for therapies against the related Human T-lymphotropic virus type 1.
Keywords: BLV; HDAC inhibitor; leukemia; HTLV
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Gillet, N.; Vandermeers, F.; de Brogniez, A.; Florins, A.; Nigro, A.; François, C.; Bouzar, A.-B.; Verlaeten, O.; Stern, E.; Lambert, D.M.; Wouters, J.; Willems, L. Chemoresistance to Valproate Treatment of Bovine Leukemia Virus-Infected Sheep; Identification of Improved HDAC Inhibitors. Pathogens 2012, 1, 65-82.
Gillet N, Vandermeers F, de Brogniez A, Florins A, Nigro A, François C, Bouzar A-B, Verlaeten O, Stern E, Lambert DM, Wouters J, Willems L. Chemoresistance to Valproate Treatment of Bovine Leukemia Virus-Infected Sheep; Identification of Improved HDAC Inhibitors. Pathogens. 2012; 1(2):65-82.
Gillet, Nicolas; Vandermeers, Fabian; de Brogniez, Alix; Florins, Arnaud; Nigro, Annamaria; François, Carole; Bouzar, Amel-Baya; Verlaeten, Olivier; Stern, Eric; Lambert, Didier M.; Wouters, Johan; Willems, Luc. 2012. "Chemoresistance to Valproate Treatment of Bovine Leukemia Virus-Infected Sheep; Identification of Improved HDAC Inhibitors." Pathogens 1, no. 2: 65-82.