Valproate activates bovine leukemia virus gene expression, triggers apoptosis, and induces leukemia/lymphoma regression in vivo.

A. Achachi, A.-F. Florins, N. Gillet, Christophe DEBACQ, Jean-Pierre Urbain, G. M. Foutsop, Fabian VANDERMEERS, A. Jasik, M. Reichert, P. Kerkhofs, L. Lagneaux, Arsène Burny, R Kettmann, L. Willems

Research output: Contribution to journalArticlepeer-review


[en] Leukemogenic viruses like human T-lymphotropic virus and bovine leukemia virus (BLV) presumably persist in the host partly by latent integration of the provirus in a fraction of infected cells, leading to accumulative increase in the outgrowth of transformed cells. Furthermore, viral infection also correlates with a blockade of the apoptotic mechanisms concomitant with an apparent latency of the host cell. Conceptually, induction of viral or cellular gene expression could thus also be used as a therapeutic strategy against retroviral-associated leukemia. Here, we provide evidence that valproate, an inhibitor of deacetylases, activates BLV gene expression in transient transfection experiments and in short-term cultures of primary B-lymphocytes. In vivo, valproate injection into newly BLV-inoculated sheep did not abrogate primary infection. However, valproate treatment, in the absence of any other cytotoxic drug, was efficient for leukemia/lymphoma therapy in the sheep model leading to decreased lymphocyte numbers (respectively from 25.6, 35.7, and 46.5 x 10(3) cells per mm3 to 1.0, 10.6, and 24.3 x 10(3) cells per mm3 in three leukemic sheep) and tumor regression (from >700 cm3 to undetectable). The concept of a therapy that targets the expression of viral and cellular genes might be a promising treatment of adult T cell leukemia or tropical spastic paraparesis/human T-lymphotropic virus-associated myelopathy, diseases for which no satisfactory treatment exists so far.
Original languageEnglish
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number29
Publication statusPublished - 2005
Externally publishedYes


  • Sciences de la santé humaine => Oncologie
  • Animals
  • Apoptosis/drug effects
  • B-Lymphocytes/metabolism
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Gene Expression Regulation, Viral/drug effects
  • Hela Cells
  • Histone Deacetylases/antagonists inhibitors
  • Humans
  • Leukemia Virus, Bovine/metabolism
  • Leukemia, Lymphoid/therapy
  • Leukocytes, Mononuclear/metabolism
  • Luciferases
  • Lymphocyte Count
  • Proviruses/metabolism
  • Remission Induction
  • Sheep
  • Valproic Acid/pharmacology/therapeutic use


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