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The Myc-evoked DNA damage response accounts for treatment resistance in primary lymphomas in vivo

Official URL:https://doi.org/10.1182/blood-2007-02-075614
PubMed:View item in PubMed
Creators Name:Reimann, M. and Loddenkemper, C. and Rudolph, C. and Schildhauer, I. and Teichmann, B. and Stein, H. and Schlegelberger, B. and Doerken, B. and Schmitt, C.A.
Journal Title:Blood
Journal Abbreviation:Blood
Volume:110
Number:8
Page Range:2996-3004
Date:15 October 2007
Keywords:Apoptosis, Ataxia Telangiectasia Mutated Proteins, Cell Cycle Proteins, B-Cell Lymphoma, Cyclin-Dependent Kinase Inhibitor p16, DNA Damage, DNA-Binding Proteins, Flow Cytometry, Gene Transfer Techniques, Genetic Transduction, Immunoblotting, myc Genes, Neoplasm Drug Resistance, Protein-Serine-Threonine Kinases, Reactive Oxygen Species, Small Interfering RNA, Tumor Suppressor Protein p53, Tumor Suppressor Proteins, Animals, Mice
Abstract: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 Emu-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.
ISSN:0006-4971
Publisher:American Society of Hematology (U.S.A.)
Item Type:Article

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