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Blood, 30 April 2009, Vol. 113, No. 18, pp. 4281-4288. Prepublished online as a Blood First Edition Paper on January 29, 2009; DOI 10.1182/blood-2008-10-183475. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2008-10-183475v1 113/18/4281    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Höglund, A. Articles by Nilsson, J. A. Search for Related Content PubMed PubMed Citation Articles by Höglund, A. Articles by Nilsson, J. A. Related Collections Lymphoid Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  LYMPHOID NEOPLASIA Myc sensitizes p53-deficient cancer cells to the DNA-damaging effects of the DNA methyltransferase inhibitor decitabine Andreas Höglund1, Lisa M. Nilsson1, Linus Plym Forshell1, Kirsteen H. Maclean1, and Jonas A. Nilsson1 1 Department of Molecular Biology, Umeå University, Umeå, Sweden Decitabine (also referred to as 5-aza-2'-deoxycytidine) is a drug that has recently been approved by the Food and Drug Administration (FDA) for the treatment of myelodysplastic syndrome (MDS). The mechanism of action is believed to be the blocking of DNA methylation and thereby reactivating silenced genes involved in harnessing MDS. When analyzing reactivation of genes involved in Burkitt lymphoma (BL), we discovered that decitabine also sensitizes tumor cells by inducing DNA damage. This sensitization is grossly augmented by the MYC oncogene, which is overexpressed in BL, and occurs in cells lacking a functional p53 tumor suppressor pathway. In p53-deficient BL cells and p53–/– mouse embryo fibroblasts, Myc overrides a transient G2-block exerted by decitabine via activation of Chk1. This triggers aneuploidy and cell death that correlates with, but can occur in the absence of, Epstein-Barr virus (EBV) reactivation, caspase activation, and/or expression of the BH3-only protein Puma. In vivo modeling of Myc-induced lymphoma suggests that decitabine constitutes a potential new drug against lymphoma that would selectively sensitize tumor cells but spare normal tissue. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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