title: Chemoresistance to Valproate Treatment of Bovine Leukemia Virus-Infected Sheep; Identification of Improved HDAC Inhibitors.
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.
authors.affiliation: Molecular and Cellular Epigenetics (GIGA) and Molecular Biology (GxABT), University of Liège, Liège 4000, Belgium. n.gillet@ulg.ac.be.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Gillet
authors.affiliation: Molecular and Cellular Epigenetics (GIGA) and Molecular Biology (GxABT), University of Liège, Liège 4000, Belgium. fabian.vandermeers@ulg.ac.be.
authors.forename: Fabian
authors.initials: F
authors.lastname: Vandermeers
authors.affiliation: Molecular and Cellular Epigenetics (GIGA) and Molecular Biology (GxABT), University of Liège, Liège 4000, Belgium. alix.debrogniez@doct.ulg.ac.be.
authors.forename: Alix
authors.initials: A
authors.lastname: de Brogniez
authors.affiliation: Molecular and Cellular Epigenetics (GIGA) and Molecular Biology (GxABT), University of Liège, Liège 4000, Belgium. florinsarnaud@hotmail.com.
authors.forename: Arnaud
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authors.lastname: Florins
authors.affiliation: Molecular and Cellular Epigenetics (GIGA) and Molecular Biology (GxABT), University of Liège, Liège 4000, Belgium. annamarianigro@hotmail.it.
authors.forename: Annamaria
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authors.lastname: Nigro
authors.affiliation: Molecular and Cellular Epigenetics (GIGA) and Molecular Biology (GxABT), University of Liège, Liège 4000, Belgium. francois-carole@hotmail.com.
authors.forename: Carole
authors.initials: C
authors.lastname: François
authors.affiliation: Molecular and Cellular Epigenetics (GIGA) and Molecular Biology (GxABT), University of Liège, Liège 4000, Belgium. amelbzr@yahoo.com.
authors.forename: Amel-Baya
authors.initials: AB
authors.lastname: Bouzar
authors.affiliation: Molecular and Cellular Epigenetics (GIGA) and Molecular Biology (GxABT), University of Liège, Liège 4000, Belgium. olivier.verlaeten@gmail.com.
authors.forename: Olivier
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authors.lastname: Verlaeten
authors.affiliation: Pharmaceutic Chemistry and Radiopharmacy Unit, Louvain Drug Research Institute, University of Louvain, Brussels 1000, Belgium. dr.eric.stern@gmail.com.
authors.forename: Eric
authors.initials: E
authors.lastname: Stern
authors.affiliation: Pharmaceutic Chemistry and Radiopharmacy Unit, Louvain Drug Research Institute, University of Louvain, Brussels 1000, Belgium. didier.lambert@uclouvain.be.
authors.forename: Didier M
authors.initials: DM
authors.lastname: Lambert
authors.affiliation: Biological Chemistry, Facultés Universitaires Notre-Dame de la Paix, Namur 5000, Belgium. johan.wouters@fundp.ac.be.
authors.forename: Johan
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authors.lastname: Wouters
authors.affiliation: Molecular and Cellular Epigenetics (GIGA) and Molecular Biology (GxABT), University of Liège, Liège 4000, Belgium. luc.willems@ulg.ac.be.
authors.forename: Luc
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authors.lastname: Willems