Research Report 2010 - MDC

Structure of the GroupClemens A. SchmittGroup LeaderProf. Dr. Clemens Schmitt, M.DScientistsDr. Soyoung Lee, Ph.D.Dr. Maurice Reimann, Ph.D.Dr. Mathias Rosenfeld, M.D.Dr. Eva Wönne, Ph.D.Bianca Teichmann, M.Sc.Graduate StudentsHenry DäbritzJan DörrJing DuAnja HaugstetterYong YuTechnical AssistantsNadine BurbachCarmen JudisSven MaßwigSandra WegenerCancer Genetics and Cellular StressResponses in Pathogenesis andTreatment of Lymphatic MalignanciesOur research program is driven by our interest in cellular stress responses (so called ‘failsafemechanisms’) that may serve as anti-tumor barriers when challenged by transformingoncogenes, and, in turn, must be bypassed or inactivated before a full-blown malignancy canactually form. Importantly, ultimate stress responses such as apoptosis or cellular senescence –both terminal ‘cell-cycle exit’ programs – do not only counter tumorigenesis, but are utilized aschemotherapy-induced stress responses as well. Hence, principles of oncogenesis andmechanisms of treatment sensitivity seem to critically overlap and impinge on each other duringtumor formation, cancer therapy and relapsed or progressive disease conditions. Moreover, recentevidence points towards interferences between cell-autonomous failsafe programs and the tumorenvironment, which, in turn, evoke feedback mechanisms that may significantly alter tumorbiology. To test the impact of genetic lesions in cellular stress response programs on tumordevelopment and treatment outcome under most physiological conditions in vivo, we generatemouse models harboring lymphomas (and other tumor entities) with defined genetic lesions.FoxO transcription factors suppress Myc-drivenlymphomagenesis via direct activation of ARFSoyoung Lee and collaboration partnersFoxO transcription factors regulate numerous cellularfunctions including proliferation, stress sensitivity, andcellular survival. Conditional co-deletion of FoxO familiymembers 1, 3 and 4 in the absence of a defined oncogenicstimulus unveiled a context-dependent cancerpronephenotype after long latencies. We investigatedin an oncogene-driven setting, namely the Eµ-myctransgenic mouse model, whether ablation of FoxOfunction via transduction of hematopoietic stem cellswith a dominant-negative FoxO moiety would give riseto accelerated tumor onset. We not only demonstrateda tumor-suppressive role of FoxO transcription factorsin Myc-induced lymphomagenesis but showed geneticallyan interference of FoxO function with the p53pathway. Precisely, we found FoxOs to bind to theINK4a/ARF locus and to induce ARF expression whenMyc is constitutively expressed. Thus, FoxO transcriptionfactors have tumor-suppressive potential and actby promoting ARF expression in response to oncogenicactivation – a pivotal pathway with FoxOs now identifiedto mediate the missing link between Myc activationand ARF induction.Oncogenic signaling evokes a DNA damageresponse that is selected against in manifestlymphomasMaurice Reimann, Ines Schildhauer, Bianca Teichmann,Bernd Dörken and collaboration partnersIn addition to the ARF/p53 pathway, the DNA damageresponse (DDR) has been recognized as another oncogene-provokedanti-cancer barrier in early humantumorigenesis leading to apoptosis or cellular senescence.DDR mutations may promote tumor formation,100 Cancer Research