In addition to the ARF/p53 pathway, the DNA damage response (DDR) has been recognized as another oncogeneprovoked 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 E-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 ϩ/ϩ -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 DDRcompetent 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. IntroductionCancer development is a process against which normal cells appear to be well protected. 1 As an early cellular barrier against imminent transformation, normal cells monitor latent oncogenic signals, which may result in activation of the ARF/p53 axis as an antiproliferative constraint, ultimately leading to apoptosis or cellular senescence. 2 In turn, genetic defects in these oncogeneinduced fail-safe programs are prerequisites for malignant conversion and thus are selected for in manifest malignancies. [3][4][5] In addition, oncogene-related cellular stress enacting a DNA damage response (DDR) has been proposed as an ARF-independent constraint to limit aberrant cell division in early tumorigenesis via induction of apoptosis or senescence. 6-10 Indeed, prototypic oncogenes such as Myc and Ras have been reported to cause DNA damage, possibly via the production of reactive oxygen species (ROS) 11,12 or by generating aberrant DNA replication intermediates. 13,14 Conversely, inherited DDR defects as known from ataxia telangiectasia (A-T), 15 the Nijmegen breakage syndrome (Nbs), 16 or the Li-Fraumeni syndrome (affecting Chk2 or p53) 17,18 predispose to cancer, presumably by facilitating mutagenic activation and permitting transforming action of mitogenic oncogenes. 19 Immunohistochemical studies on epithelial tumor specimens of various developmental stages driven by unspecified oncogenic moieties found hyperproliferative precursor lesions to display activated components of the Atr/Nbs1/Chk1 and the Atm/Chk2/p53 DDR cascades, whereas this activation was lost in more advanced neoplastic lesions, thereb...

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The functional expression of costimulatory molecules on antigen-presenting cells may be a key event in the pathogenesis of atopic dermatitis (AD). Recently, the expression of CD86 (B7-2/B70) has been demonstrated on CD1a+ epidermal dendritic cells (DC) in AD lesions by immunohistological and functional analysis. Therefore, we sought to further characterize the in situ expression of costimulatory molecules on these cells, considering the two subpopulations of (1) CD1a+++/CD11b- Langerhans cells (LC) containing Birbeck granules and (2) CD1a+/CD11b+++ inflammatory dendritic epidermal cells (IDEC), devoid of Birbeck granules, from AD and other inflammatory skin diseases. Flow cytometry, skin mixed lymphocyte reactions (SMLR) and immunohistological analysis were performed, and showed that IDEC and not LC are the relevant cells expressing the costimulatory molecules CD80 and CD86 in situ. This expression varied with the underlying diagnosis, with AD showing the highest expression of both CD80 and CD86 in situ. Furthermore, the expression of CD80, CD86 and CD36 were significantly correlated. With short-term culture, both CD80 and CD86 were further upregulated on LC and IDEC. Finally, anti-CD86 antibody reduced the stimulatory activity of epidermal DC. These results indicate that costimulatory molecules on LC and IDEC might play a role in the pathogenesis of AD.

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