The mammalian target of rapamycin (mTOR) signaling in thymic lymphomagenesis in Atm-/- mice

AACR Centennial Conference: Translational Cancer Medicine-- July 20-23, 2008; Monterey, CA A34 The mammalian target of rapamycin (mTOR) signaling in thymic lymphomagenesis in Atm-/- mice Loss of ATM function leads to the human disease Ataxia Telengiectasia (A-T). One of the major characteristics of A-T is predisposition to lymphoid malignancies. In normal individuals, inactivation of the Atm gene or its gene product, ATM, is also associated with sporadic lymphoid tumors. Apparently, ATM plays a critical role in controlling the development of such tumors, although the mechanisms are still not clear. ATM, in addition to its role in DNA repair, regulates cellular redox status and cell cycling. Accumulation of reactive oxygen species (ROS), from either endogenous or environmental sources, is termed oxidative stress, leading to DNA damage, genomic instability, cell death and cancer. We have previously demonstrated that during thymic development levels of ROS, DNA synthesis, and the oncoprotein c-Myc are all increased in Atm -/- thymocytes. We hypothesize that the increase in ROS levels contributes to the elevation of DNA synthesis and the increased levels of c-Myc in these cells, because treatment with antioxidants attenuates all three. In this study, we have attempted to determine how ATM/ROS regulate thymocyte development. The evolutionarily conserved checkpoint protein kinase, mTOR, controls proliferation, differentiation, migration, and survival of cells by regulating protein synthesis. Because c-Myc is critical for thymocyte development, we reasoned that mTOR, as a controller of c-Myc, may play an important role in regulating this process. Using 3H-TdR incorporation into DNA, we found that mTOR inhibition by its specific inhibitor rapamycin suppresses thymocyte DNA synthesis both, in vitro and in vivo, suggesting that the mTOR signaling is essential for thymocyte proliferation. In Atm-/- mice, we showed that the downstream molecule of mTOR, 4E-BP1, is highly phosphorylated in their thymocytes, and that mTOR target proteins, c-Myc and cyclin D1, are coordinately increased. These results suggest that ATM may regulate thymocyte development by counteracting mTOR signaling. We further showed that rapamycin attenuates elevation of phospho-4E-BP1 and cyclin D1 in Atm-/- thymocytes, and prevents thymic lymphomagenesis in the animals. Interestingly, H2O2 regulates 4EBP1, S6K and eIF4G phosphorylation in Atm+/+ and Atm-/- thymocytes. Our findings are the first to show the mTOR pathway participates in controlling thymocyte development. We are also the first to show that the mTOR inhibitor rapamycin prevents thymic lymphomagenesis in Atm -/- mice, whose thymocyte development is abnormal. These findings, identifying the mTOR signaling as potential therapeutic targets for treatment of thymic lymphoma in A-T patients, may also shed light on targeting the mTOR pathway as treatment for other cancers.