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Acute Non-Lymphocytic Leukemia

The histone deacetylase inhibitor valproic acid alters sensitivity towards all trans retinoic acid in acute myeloblastic leukemia cells

Leukemia volume 19, pages 1161–1168 (2005)Cite this article

Abstract

Acute myeloblastic leukemia (AML) may be classified in a number of ways. Using the French American British classification, the M3 form of the disease or acute promyelocytic leukemia (APL) has been found to be sensitive in vitro and in vivo to the retinoid all trans retinoic acid (ATRA). The mechanism for this is by restoration of normal gene expression through the release of histone deacetylase complexes (HDACs). In contrast to APL, other forms of AML are either nonresponsive or show blunted responses to ATRA. We evaluated if the inhibitor of HDAC activity, valproic acid (VPA), could mimic or enhance retinoid sensitivity in the AML cell line, OCI/AML-2, and clinical samples derived from patients with AML. An Affymetrix GeneChip experiment demonstrated that VPA modulated the expression of numerous genes in OCI/AML-2 cells that were not affected by ATRA including p21, a retinoid responsive gene in APL. VPA induced p21 expression in OCI/AML-2 cells and the majority of the AML samples tested; this was associated with cell cycle arrest and apoptosis not seen with ATRA alone. The addition of ATRA to VPA accentuated many of these responses, supporting the potential beneficial combination of these drugs in the treatment of AML.

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Acknowledgements

This work was supported by grants from the Leukemia Research Fund of Canada and the National Cancer Institute of Canada. MDM is the Philip Orsino Chair in Leukemia Research at the Princess Margaret Hospital/University Health Network. MR Trus was supported through the Leukemia Research Fund of Canada.

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Authors and Affiliations

  1. Department of Medical Biophysics, Princess Margaret Hospital/Ontario Cancer Institute University Health Network, Toronto, Ontario, Canada

    M R Trus, L Yang, F Suarez Saiz & M D Minden

  2. Department of Medical Oncology, Mount Sinai Hospital, Toronto, Ontario, Canada

    L Bordeleau

  3. Division of Cancer Informatics, Princess Margaret Hospital/Ontario Cancer Institute University Health Network, Toronto, Ontario, Canada

    I Jurisica

  4. Department of Medical Oncology and Hematology, Princess Margaret Hospital/Ontario Cancer Institute University Health Network, Toronto, Ontario, Canada

    M D Minden

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  1. M R Trus
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  2. L Yang
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  6. M D Minden
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Corresponding author

Correspondence to M D Minden.

Additional information

For simplicity of nomenclature, the M3 form of leukemia will be referred to as acute promyelocytic leukemia (APL) and non-APL forms of acute myeloblastic leukemia (AML) will be referred to as AML. p21=p21WAF1/KIP.

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

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Trus, M., Yang, L., Suarez Saiz, F. et al. The histone deacetylase inhibitor valproic acid alters sensitivity towards all trans retinoic acid in acute myeloblastic leukemia cells. Leukemia 19, 1161–1168 (2005). https://doi.org/10.1038/sj.leu.2403773

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