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Chronic Lymphocytic Leukemia

Antileukemic activity of valproic acid in chronic lymphocytic leukemia B cells defined by microarray analysis

Leukemia volume 23, pages 2281–2289 (2009)Cite this article

Abstract

Epigenetic code modifications by histone deacetylase inhibitors have recently been proposed as potential new therapies for hematological malignancies. Chronic lymphocytic leukemia (CLL) remains incurable despite the introduction of new treatments. CLL B cells are characterized by an apoptosis defect rather than excessive proliferation, but proliferation centers have been found in organs such as the bone marrow and lymph nodes. In this study, we analyzed gene expression modifications in CLL B cells after treatment with valproic acid (VPA), a well-tolerated anti-epileptic drug with HDAC inhibitory activity. CLL B cells obtained from 14 patients were treated in vitro with a concentration of 1 mM VPA for 4 h. VPA effects on gene expression were thereafter studied using Affymetrix technology, and some identified genes were validated by real-time PCR and western blot. We observed that VPA induced apoptosis by downregulating several anti-apoptotic genes and by upregulating pro-apoptotic genes. Furthermore, VPA significantly increased chemosensitivity to fludarabine, flavopiridol, bortezomib, thalidomide and lenalidomide. VPA inhibited the proliferation of CpG/IL2-stimulated CLL B cells and modulated many cell cycle messenger RNAs. In conclusion, exposure of CLL B cells to VPA induced apoptosis, potentiated chemotherapeutic agent effects and inhibited proliferation. These data strongly suggest the use of VPA in CLL treatment, particularly in combination with antileukemia agents.

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Acknowledgements

This work was financed by FRIA grant (Fonds de Recherche pour l’Industrie et l’Agriculture) and the Télévie fund, both of which are affiliated with the FRS–FNRS (Fonds de la Recherche Scientifique–FNRS) and by the ‘Fédération belge contre le cancer’. BS (FRIA fellow), CD (scientific research worker) and LL (senior research associate) are members of the FNRS. BS performed the research, analyzed the data, made the figures and tables, performed statistical analysis, and wrote the paper. NM, DB and PM contributed to patient samples and data. CD contributed to flow cytometry experiments. LL designed, supervised the research, corrected and revised the paper.

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Authors and Affiliations

  1. Laboratory of Experimental Hematology, Faculty of Medicine, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium

    B Stamatopoulos, N Meuleman, C De Bruyn, P Martiat, D Bron & L Lagneaux

  2. Department of Hemato-Oncology, Hôpital Saint-Joseph, Gilly, Belgium

    P Mineur

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  1. B Stamatopoulos
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  2. N Meuleman
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Correspondence to B Stamatopoulos.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Stamatopoulos, B., Meuleman, N., De Bruyn, C. et al. Antileukemic activity of valproic acid in chronic lymphocytic leukemia B cells defined by microarray analysis. Leukemia 23, 2281–2289 (2009). https://doi.org/10.1038/leu.2009.176

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