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

Abstract

[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
Volume102
Issue number29
DOIs
Publication statusPublished - 2005
Externally publishedYes

Keywords

  • 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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