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Blood, 15 October 2007, Vol. 110, No. 8, pp. 2996-3004. Prepublished online as a Blood First Edition Paper on June 11, 2007; DOI 10.1182/blood-2007-02-075614. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-02-075614v1 110/8/2996    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 HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Reimann, M. Articles by Schmitt, C. A. Search for Related Content PubMed PubMed Citation Articles by Reimann, M. Articles by Schmitt, C. A. Related Collections Neoplasia Oncogenes and Tumor Suppressors Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA The Myc-evoked DNA damage response accounts for treatment resistance in primary lymphomas in vivo Maurice Reimann1, Christoph Loddenkemper2, Cornelia Rudolph3, Ines Schildhauer1, Bianca Teichmann1, Harald Stein2, Brigitte Schlegelberger3, Bernd Dörken1,4, and Clemens A. Schmitt1,4 1 Charité–Humboldt University, Campus Virchow, Department of Hematology/Oncology, Berlin; 2 Charité–Humboldt University, Campus Benjamin Franklin, Department of Pathology, Berlin; 3 Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover; and 4 Max-Delbrück-Center for Molecular Medicine, Berlin, Germany In addition to the ARF/p53 pathway, the DNA damage response (DDR) has been recognized as another oncogene-provoked anticancer barrier in early human tumorigenesis leading to apoptosis or cellular senescence. DDR mutations may promote tumor formation, but their impact on treatment outcome remains unclear. In this study, we generated ataxia telangiectasia mutated (Atm)–proficient and -deficient B-cell lymphomas in Eµ-myc transgenic mice to examine the role of DDR defects in lymphomagenesis and treatment sensitivity. Atm inactivation accelerated development of lymphomas, and their DNA damage checkpoint defects were virtually indistinguishable from those observed in Atm+/+-derived lymphomas that spontaneously inactivated the proapoptotic Atm/p53 cascade in response to Myc-evoked reactive oxygen species (ROS). Importantly, acquisition of DDR defects, but not selection against the ARF pathway, could be prevented by lifelong exposure to the ROS scavenger N-acetylcysteine (NAC) in vivo. Following anticancer therapy, DDR-compromised lymphomas displayed apoptotic but, surprisingly, no senescence defects and achieved a much poorer long-term outcome when compared with DDR-competent lymphomas treated in vivo. Hence, Atm eliminates preneoplastic lesions by converting oncogenic signaling into apoptosis, and selection against an Atm-dependent response promotes formation of lymphomas with predetermined treatment insensitivity. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. Hoglund, L. M. Nilsson, L. P. Forshell, K. H. Maclean, and J. A. Nilsson Myc sensitizes p53-deficient cancer cells to the DNA-damaging effects of the DNA methyltransferase inhibitor decitabine Blood, April 30, 2009; 113(18): 4281 - 4288. [Abstract] [Full Text] [PDF] J H-C Ho, K-C Tseng, W-H Ma, K-H Chen, O K-S Lee, and Y Su Thymosin beta-4 upregulates anti-oxidative enzymes and protects human cornea epithelial cells against oxidative damage Br J Ophthalmol, July 1, 2008; 92(7): 992 - 997. [Abstract] [Full Text] [PDF] C. Bouchard, S. Lee, V. Paulus-Hock, C. Loddenkemper, M. Eilers, and C. A. Schmitt FoxO transcription factors suppress Myc-driven lymphomagenesis via direct activation of Arf Genes & Dev., November 1, 2007; 21(21): 2775 - 2787. [Abstract] [Full Text] [PDF]

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