Research Report 2010 - MDC

ACBDMyc and FoxO transcription factors co-operate in tumor-suppressiveARF induction. We tested the questions whether FoxO transcriptionfactors possess tumor-suppressive potential in Myc-driven tumordevelopment and whether a dominant-negative FoxO moiety(dnFoxO) may act via interference with the ARF/p53 pathway (A). Eµmyctransgenic, p53 +/+ or p53 +/- hematopoietic stem cells were stablytransduced with dnFoxO or mock, and lymphoma onset was monitored.Note that p53 +/+ ,dnFoxO lymphomas formed much faster thancontrols (i.e. p53 +/+ lymphomas without dnFoxO), and arose virtuallyindistinguishable from the p53 +/- group were lymphomas typically losethe remaining p53 allele (‘p53null’) (B). ARF expression is detectable inlymphoma sections independent of their p53 status, but only in theabsence of the dnFoxO moiety (C). FoxO transcription factors bind tothe FBS2 consensus site in the INK4a/ARF promoter, but only inductionof Myc, not activation of FoxOs by the PI3 kinase inhibitor LY294002(both resulting in equal binding of FoxOs to FBS2 [data not shown]),promote ARF expression (D).but their impact on treatment outcome remainsunclear. In this study, we generated Atm (ataxia telangiectasiamutated)-proficient and -deficient B-cell lymphomasin Eµ-myc transgenic mice to examine the roleof DDR defects in lymphomagenesis and treatmentsensitivity. Atm inactivation accelerated developmentof lymphomas, and their DNA damage checkpointdefects were virtually indistinguishable from thoseobserved in Atm +/+ -derived lymphomas that spontaneouslyinactivated the pro-apoptotic Atm/p53 cascadein response to Myc-evoked reactive oxygen species(ROS). Importantly, acquisition of DDR defects, but notselection against the ARF pathway, could be preventedby lifelong exposure to the ROS scavenger N-acetyl-cysteine(NAC) in vivo. Following anticancer therapy, DDRcompromisedlymphomas displayed apoptotic, but, surprisingly,no senescence defects, and achieved a muchpoorer long-term outcome when compared to DDRcompetentlymphomas treated in vivo. Hence, Atmeliminates pre-neoplastic lesions by converting oncogenicsignaling into apoptosis, and selection against anAtm-dependent response promotes formation of lymphomaswith predetermined treatment insensitivity.Apoptotic lymphoma cells trigger TGF-β secretionof host macrophages that results in tumorsuppressivelymphoma cell senescenceMaurice Reimann, Soyoung Lee, Jan Dörr, Bernd Dörkenand collaboration partnersActivated RAS/BRAF oncogenes induce cellular senescenceas a tumor suppressive barrier in early cancerdevelopment – as recently demonstrated by our group(Braig et al., Nature, 2005) – at least in part, via an oncogene-evokedDNA damage response (DDR). In contrast,Myc activation – although producing a DDR as well – isknown to primarily elicit an apoptotic countermeasure.Using the Eµ-myc transgenic mouse lymphoma model,we found that both a cell-autonomous DDR-dependentand a non-cell-autonomous transforming growth factor–(TGF-β)-mediated induction of cellular senescencelimits Myc-driven tumor development. While acuteinduction of Myc signaling is sufficient to produce lymphomacell senescence in vitro, we identified TGF-β asthe pivotal senescence trigger in vivo. We demonstratethat TGF-β is not secreted by lymphoma cells but isdelivered by macrophages upon their activation byapoptotic lymphoma cells. These findings, detectable inhuman aggressive B-cell lymphomas as well, establisha novel network of heterotypic cell-cell interactions inwhich apoptotic tumor cells launch a paracrineresponse in non-malignant bystanders that limitstumorigenesis by cellular senescence.Selected PublicationsBouchard*, C., S. Lee*, V. Paulus-Hock, C. Loddenkemper, M. Eilers and C.A.Schmitt. 2007. FoxO transcription factors suppress Myc-driven lymphomagenesisvia direct activation of ARF. Genes Dev. 21: 2775-2787. *) equalcontributionKilic, M. and C.A. Schmitt. 2008. Exploiting drug-induced senescence intransgenic mouse models. In Beyond apoptosis – cellular outcomes ofcancer therapy; edited by Roninson, I.B., J. M. Brown and D.E. Bredesen.Informa Health Care USA, Inc. – New York, London: 273-294.Reimann, M., C. Loddenkemper, C. Rudolph, I. Schildhauer, B. Teichmann, H.Stein, B. Schlegelberger, B. Dörken and C.A. Schmitt. 2007. The Myc-evokedDNA damage response accounts for treatment resistance in primary lymphomasin vivo. Blood 110: 2996-3004.Reimann, M., C. Loddenkemper, S. Lee, Dörr, J., Tabor, P. Aichele, V., H. Stein,B. Dörken, T. Jenuwein and C.A. Schmitt. 2009. Tumor-stroma-derived TGF-βlimits Myc-driven lymphomagenesis via Suv39h1-dependent senescence.In press.Schmitt, C.A. 2007. Cellular senescence and cancer treatment. Biochim.Biophys. Acta 1775: 5-20.Cancer Research 101