AP-1 in lymphoma formation

Group Leader:
Prof. Dr. Lukas Kenner

Contact:
Institute for Clinical Pathology
Medical University Vienna
Währingergürtel 18-20
A-1090 Vienna
mobile:  +43 664 1188385
phone: +43 1 404004650 (secretary)
lukas.kenner@meduniwien.ac.at

Afiliation:
Ludwig Boltzmann Institute for Cancer Research (LBI-CR)
Währingerstrasse 13A
phone: +43 1 427764111
fax: +43 1 42779641

Funding:
Ludwig Boltzmann Gesellschaft
FWF
Bürgermeister Fonds der Stadt Wien

Description: ALCL is a highly malignant form of Non-Hodgkin’s lymphoma and frequently associated with a chromosomal translocation generating the oncogenic fusion protein NPM-ALK. We take advantage of a NPM-ALK transgenic mouse model for ALCL lymphomagenesis driven by the human CD4 promoter (Chiarle et al. 2003). These mice develop high malignant T-cell lymphomas. 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. We use mice carrying floxed alleles of JunB and/or c-Jun and the CD4-Cre mice which specifically delete these genes in T-cells. We conditionally delete c-Jun and JunB in NPM-ALK induced lymphomas to study the requirement of AP-1 in lymphoma formation. In this context we analyze latency, proliferation and the apoptotic index of transformed cells. These experiments define the function of AP-1 targets as potential therapeutic target in T-cell lymphomas before and/or after lymphoma formation. 

Collaborators:
Olaf Merkel (Salzburg), Suzanne Turner (Cambridge), Giorgio Inghirami (Turino)

Publications:
1- Merkel O., Hamacher F., Laimer D., Trajanoski Z., Scheideler M., Egger G.,. Hassler M.R., Thallinger C., Schmatz A., Turner S.D., Greil R. and Kenner L. Identification of differential and functionally active miRNAs in both ALK+ and ALK- anaplastic large cell lymphoma.
PNAS 2010 107(37):16228-33.
2- Meixner A., Zenz R, Schonthaler HB., Kenner L., Scheuch, H., Penninger, JM., Wagner, EF. Epidermal JunB represses G-CSF synthesis and controls hematopoiesis and bone formation.
Nature Cell Biol., 10:1003-11 2008.
3- Staber P., Vesely P., Haq N., Ott R., Funato K., Bambach I., Fuchs C., Schauer S., Linkesch W, Hrzenja A.,. Dirks W.G., Sexl V., Bergler H., Kadin M.E.,. Sternberg D., Kenner L., and Hoefler G.
Blood 110: 3374-83 2007.
4- Staber P.B., Noehammer C., Durkop H., Schauer S., Kenner L., Linkesch W., and Hoefer G. Leuk. Res. 30:343-8 2006.
Kenner L., Hoebertz A., Eferl R., Beil F.T., Amling M., Keon N., Schorpp-Kistner M., Angel P. and Wagner E.F.
J. Cell Biol. 2004 164: 613-623.

Weblinks: http://lbicr.lbg.ac.at/en/research-group/lukas-kenner

Tools:
CD4creNPM-ALK transgenic mice, JunB and c-Jun floxed mice, ALCL cell lines (human and mouse), paraffin embedded and frozen ALCL patient samples

Techniques:
Conditional mouse technology
Xenograft mouse models
Phenotyping and quantitative Histomorphometry
Molecular Pathology