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

Blood - Tập 110 - Trang 2996-3004 - 2007
Maurice Reimann1, Christoph Loddenkemper2, Cornelia Rudolph3, Ines Schildhauer1, Bianca Teichmann1, Harald Stein2, Brigitte Schlegelberger3, Bernd Dörken1,4, Clemens A. Schmitt1,5
1Charité–Humboldt University, Campus Virchow, Department of Hematology/Oncology, Berlin
2Charité–Humboldt University, Campus Benjamin Franklin, Department of Pathology, Berlin
3Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover;
4Max Delbrück Center for Molecular Medicine, Berlin, Germany
5Max-Delbrück-Center for Molecular Medicine, Berlin, Germany

Tóm tắt

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 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.


Tài liệu tham khảo

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