The role of c-Jun and JunB for lymphoma development

ALCL, a highly malignant form of Non-Hodgkin`s lymphoma, is frequently associated with a chromosomal translocation generating the oncogenic fusion protein NPM-ALK. A transgenic mouse model of lymphomagenesis in which transcription of a human NPM-ALK construct was targeted to T cells was recently described. These mice develop thymic T-cell lymphomas and also B-cell neoplasms with plasmacytic differentiation. Human ALCLs were recently shown to constitutively overexpress the AP-1 proteins c-Jun and JunB. Jun proteins are regulated by Jun-aminoterminal phosphorylation (JNP) through Jun-aminoterminal kinases (JNKs) and can induce transformation. Interestingly, a tumor suppressive role of JunB was recently demonstrated in mice lacking JunB in the myeloid lineage which develop a CML-like disease. The goals of the present study are: 1. We want to analyse the effect of ALK on the MAPK signal transduction pathway and on AP-1 activity using ALK positive and negative lymphoma cell lines as well as cell lines transfected with active and inactive forms of NPM-ALK kinase. In addition, we want to analyse the composition of AP-1 dimers that bind to AP-1 consensus oligonucleotide in ALK positive lymphoma cell lines. 2. We intend to study the requirement for c-Jun in lymphoma formation using conditional deletion of c-Jun in NPM-ALK induced lymphomas. In this context we want to analyse the latency, proliferation and the apoptotic index of transformed cells. This study should define the function of c-Jun as a potential therapeutic target in T-cell lymphoma formation. 3. 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. 4. We intend to knock down the expression of c-Jun and JunB in human ALCL derived cell lines. Xenograft experiments with these cells will be performed to elucidate the relevance of our studies done in mice on human lymphoma formation

ALCL, a highly malignant form of Non-Hodgkin`s lymphoma, is frequently associated with a chromosomal translocation generating the oncogenic fusion protein NPM-ALK. A transgenic mouse model of lymphomagenesis in which transcription of a human NPM-ALK construct was targeted to T cells was recently described. These mice develop thymic T-cell lymphomas and also B-cell neoplasms with plasmacytic differentiation. Human ALCLs were recently shown to constitutively overexpress the AP-1 proteins c-Jun and JunB. Jun proteins are regulated by Jun-aminoterminal phosphorylation (JNP) through Jun-aminoterminal kinases (JNKs) and can induce transformation. Interestingly, a tumor suppressive role of JunB was recently demonstrated in mice lacking JunB in the myeloid lineage which develop a CML-like disease. The goals of the present study are: 1. We want to analyse the effect of ALK on the MAPK signal transduction pathway and on AP-1 activity using ALK positive and negative lymphoma cell lines as well as cell lines transfected with active and inactive forms of NPM-ALK kinase. In addition, we want to analyse the composition of AP-1 dimers that bind to AP-1 consensus oligonucleotide in ALK positive lymphoma cell lines. 2. We intend to study the requirement for c-Jun in lymphoma formation using conditional deletion of c-Jun in NPM-ALK induced lymphomas. In this context we want to analyse the latency, proliferation and the apoptotic index of transformed cells. This study should define the function of c-Jun as a potential therapeutic target in T-cell lymphoma formation. 3. 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. 4. We intend to knock down the expression of c-Jun and JunB in human ALCL derived cell lines. Xenograft experiments with these cells will be performed to elucidate the relevance of our studies done in mice on human lymphoma formation.