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Blood, 15 February 2008, Vol. 111, No. 4, pp. 2190-2199. Prepublished online as a Blood First Edition Paper on November 1, 2007; DOI 10.1182/blood-2007-06-093682. This Article Full Text (PDF) All Versions of this Article: blood-2007-06-093682v1 111/4/2190    most recent Alert me when this article is cited Alert me if a correction is posted 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 HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Krejci, O. Articles by Mulloy, J. C. Search for Related Content PubMed PubMed Citation Articles by Krejci, O. Articles by Mulloy, J. C. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted June 4, 2007 Accepted October 23, 2007 p53 signaling in response to increased DNA damage sensitizes AML1-ETO cells to stress-induced death Ondrej Krejci, Mark Wunderlich, Hartmut Geiger, Fu-Sheng Chou, David Schleimer, Michael Jansen, Paul R. Andreassen, and James C. Mulloy* Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, United States Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, United States * Corresponding author; email: james.mulloy{at}cchmc.org. Chromosomal translocation 8;21 is present in 10-15% of patients with acute myeloid leukemia. Expression of the AML1-ETO (AE) fusion protein alone is not sufficient to induce leukemia, but the nature of the additional genetic alterations are unknown. It is unclear whether AE facilitates acquisition of these cooperating events. We show that AE downregulates genes involved in multiple DNA repair pathways, potentially through a mechanism involving direct binding at promoter elements, and increases the mutation frequency in vivo. AE cells display increased DNA damage in vitro and have an activated p53 pathway. This results in increased basal apoptosis and enhanced sensitivity to DNA damaging agents compared to control cells. Intriguingly, microarray data indicate that t(8;21) patient samples exhibit decreased expression of DNA repair genes and increased expression of p53 response genes when compared to other AML patient samples. Inhibition of the p53 pathway by RNAi increases the resistance of AE cells to DNA damage. We thus speculate that AML1-ETO may facilitate accumulation of genetic alterations by suppressing endogenous DNA repair. It is possible that the superior outcome of t(8;21) patients is partly due to an activated p53 pathway, and that loss of the p53 response pathway is associated with disease progression. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: New role for AML1/ETO in leukemogenesis Martin Carroll Blood 2008 111: 1752. [Full Text] [PDF] This article has been cited by other articles: J. Zuber, I. Radtke, T. S. Pardee, Z. Zhao, A. R. Rappaport, W. Luo, M. E. McCurrach, M.-M. Yang, M. E. Dolan, S. C. Kogan, et al. Mouse models of human AML accurately predict chemotherapy response Genes & Dev., April 1, 2009; 23(7): 877 - 889. [Abstract] [Full Text] [PDF] T. Berg, M. Fliegauf, J. Burger, M. S. Staege, S. Liu, N. Martinez, O. Heidenreich, S. Burdach, T. Haferlach, M. H. Werner, et al. Transcriptional upregulation of p21/WAF/Cip1 in myeloid leukemic blasts expressing AML1-ETO Haematologica, November 1, 2008; 93(11): 1728 - 1733. [Abstract] [Full Text] [PDF]

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