Research Report 2010 - MDC

Angela MensenStefanie WittstockBjörn LamprechtKarl KöchertShuang LiKatrin UllrichKathrin D. WursterTechnical AssistantsKerstin GerlachSimone KressmannFranziska HummelBrigitte Wollert-WulfUte Nitschke*part of the period reportedBcl-3 might be involved in apoptosis protection of thesecells. Furthermore, we have shown that AP-1 is involvedin the dedifferentiation process of HRS cells by maintaininghigh expression of the E2A antagonist inhibitorof differentiation 2 (Id2), and the overexpression of theAP-1 family member Fra2 in ALCL cells contributes totheir malignant transformation. The AP-1 activity mightfurther be enhanced by a specific overexpression of theCREB family member ATF3. ATF3 is specifically overexpressedin HRS and ALCL tumor cells and protects atleast HRS cells from apoptosis. In addition, we showedthat p53-dependent apoptosis can be induced in HRScells by the MDM2-antagonist nutlin-3, and thus theactivation of the p53 pathway might represent a noveltreatment strategy for cHL. These data provide insightsinto the deregulated apoptosis and survival signalingpathways in HRS cells.Analysis of the mechanisms leading to formationof the ALCL-specific translocation t(2;5)(p23;q35)S. Mathas, B. Dörken in cooperation with T. Misteli (NCI,Bethesda)Whereas the identification and characterization oftranslocations rapidly increases, little is known aboutthe mechanisms how translocations occur in vivo.Using anaplastic large cell lymphoma (ALCL) with andwithout the characteristic non-random translocationt(2;5)(p23;q35) as model system, we study the mechanismsof formation of t(2;5)(p23;q35) translocations inthese cells. We could show that several genes surroundingthe ALCL translocation breakpoint are deregulatedregardless of whether the tumor contains the t(2;5). Theaffected genes include the oncogenic transcription factorFra2 (located on 2p23), the HLH protein Id2 (2p25)and the oncogenic tyrosine kinase CSF1-receptor(5q33.1), and their up-regulation promotes cell survivaland repression of T cell-specific gene expression programs,a feature that is characteristic for ALCL. By 3Dinterphase FISH analyses we demonstrated that thederegulated genes are in spatial proximity within thenuclear space of t(2;5)-negative ALCL cells, facilitatingtheir translocation. These data suggest that deregulationof breakpoint proximal genes occurs prior to formationof translocation and that aberrant transcriptionalactivity of genome regions is linked to theirpropensity to undergo chromosomal translocations.How to deliver cytotoxic agents during effector Tcell mediated adaptive immune responsesA. Rehm, B. Dörken in cooperation with U.E. Höpken, T.Willnow, MDCEstrogen plays a critical role in the regulation of growth,development and cell type-specific gene expression invarious tissues, including the immune system.Alterations in the response to estrogen are associatedwith hormone-dependent diseases, such as breast andovarian cancer. Adjuvant therapies with estrogenreceptorinhibitors mounted to a tremendous improvementof tumor-free survival among patients, which wasexplained primarily through the inhibition of the proproliferativeeffect of estrogen in tumor cells itself.However, implications for a concurrent impact on theimmune system remained unclear. We have characterizedan estrogen-inducible tumor-associated antigen,EBAG9, through engineered deletion of the gene inmice.In cytotoxic T lymphocytes from these mice, equippedwith lytic granules that undergo polarized transportand exocytosis in a Ca 2+ -dependent manner, release ofcytolytic mediators was enhanced, an effect that translatedinto the rapid clearance of intracellular bacteria.Furthermore, a tumor-peptide labeled target cell populationwas eliminated in an accelerated fashion. Thus,under physiological conditions EBAG9 tempers lymphocytekilling activity. Upon estrogen-induced enhancedgene expression, EBAG9 could act as an inhibitor offull effector T cell activation with an ensuing lack ofimmunosurveillance.While the function of the neuronal sorting receptorsSorLA/LR11 and Sortilin within the neuronal system hasbeen well established, little is known about their role inthe immune system. In a Sortilin-genetically deletedmouse strain we have elucidated that this sortingreceptor plays a pivotal and non-redundant role duringthe cytotoxic effector function. However, unlike EBAG9-Cancer Research 127