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Die Rolle von c-Jun und JunB für die Lymphomenstehung
- Abstract
- ALCL, a highly malignant form of Non-Hodgkins lymphoma, is frequently associated with a chromosomal translocation generating the oncogenic fusion protein NPM-ALK. A NPM-ALK transgenic mouse model of lymphomagenesis was recently described. These mice develop thymic T-cell lymphomas and also B-cell neoplasms with plasmablastic differentiation. Human ALCLs were recently shown to constitutively overexpress the AP-1 proteins c-Jun and JunB. The role of c-Jun and JunB in T-cell lymphomas has not been fully understood. Interestingly, a tumor suppressive role of JunB was recently demonstrated in mice lacking JunB in the myeloid lineage which develop a CML-like disease. In the proposed project we take advantage of mice carrying floxed alleles of JUNB and c-JUN and the Lck-Cre or CD4-Cre mice which specifically delete these genes in T-cells. Therefore we will be able to further investigate the role of proto-oncogene c-JUN and the anti-oncogene JUNB in NPM-ALK mediated T-cell malignancies in vivo.
Here we further want to analyse the effect of NPM-ALK on the MAPK signal transduction pathway and on AP-1 activity using NPM-ALK positive and negative lymphoma cell lines. We determine also the composition of AP-1 dimers that bind to AP-1 DNA binding elements in cell lines.
Next we are using conditional deletion of c-Jun in NPM-ALK induced lymphomas to study the requirement for c-Jun in lymphoma formation. In this context we want to analyse the latency, proliferation and the apoptotic index of transformed cells. These experiments will define the function of c-Jun as a potential therapeutic target in T-cell lymphomas before or after lymphoma formation. A conditional loss of function approach whereby JunB and/or c-Jun are specifically deleted in T-cells of NPM-ALK transgenic mice will be employed to define the functions of these two proteins in T cell transformation.
We also intend to stably knock down the expression of c-Jun and JunB in human ALCL derived cell lines. To elucidate the relevance of our studies done in mice on human lymphoma formation, we will then perform Xenograft experiments using these cell lines.
- Keywords
- experimental pathology
- medical molecular biology
- ALCL
- c-Jun
- JunB
- Lymphoma development
- Local Subprojectlead:
- Kenner Lukas
- Höfler Gerald
- Duration:
- 01.04.2006-31.03.2009
- Programme:
- Einzelprojekt
- Type of Research
- basic research
- Staff
- Kenner, Lukas, Project Leader
- Höfler, Gerald, Project Leader
- MUG Research Units
- Diagnostic and Research Institute of Pathology
- Funded by
- FWF, Fonds zur Förderung der Wissenschaftlichen Forschung, Wien, Austria
FWF-Grant-DOI: 10.55776/P18478
- Project results published
- > A kinase-independent function of CDK6 links the ce... Cancer Cell. 2013; 24(2):167-181