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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 (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 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. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted February 21, 2007 Accepted May 29, 2007 The Myc-evoked DNA damage response accounts for treatment resistance in primary lymphomas in vivo Maurice Reimann, Christoph Loddenkemper, Cornelia Rudolph, Ines Schildhauer, Bianca Teichmann, Harald Stein, Brigitte Schlegelberger, Bernd Dorken, and Clemens A. Schmitt* Hematology/Oncology, Charite- Humboldt University, Campus Virchow, Berlin, Germany Pathology, Charite-Humboldt University, Campus Benjamin Franklin, Berlin, Germany Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany Max-Delbruck-Center of Molecular Medicine, Berlin, Germany * Corresponding author; email: clemens.schmitt{at}charite.de. In addition to the ARF/p53 pathway, the DNA damage response (DDR) has been recognized as another oncogene-provoked anti-cancer 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 Atm (ataxia telangiectasia mutated)-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 pro-apoptotic Atm/p53 cascade in response to Myc-evoked reactive oxygen species. Importantly, acquisition of DDR defects, but not of 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 to DDR-competent lymphomas treated in vivo. Hence, Atm eliminates pre-neoplastic 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: 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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