University of Veterinary Medicine, Vienna Institute of Pathology and Forensic Veterinary Medicine

Abstract: Dissecting PDGFRB function in NPM- ALK driven lymphoma

Lukas KENNER, Pathology of Laboratory Animals

The study of tumor animal models of proven clinical relevance is essential to advance clinical practice. Anaplastic large cell lymphoma (ALCL) is a malignant T-cell Non-Hodgkin lymphoma and frequently associated with the t(2;5) translocation resulting in expression of the Nucleophosmin-Anaplastic Lymphoma Kinase (NPM-ALK) fusion . Recent studies by us identified AP-1 transcription factors (TF) JUNB and cJUN as downstream effectors of NPM-ALK. These TFs directly upregulate platelet derived growth factor B (PDGFRB) expression in lymphoma cells. Based on these findings we established a mouse model for ALCL by expressing NPM-ALK under the CD4 promoter, which is the only animal model reflecting the clinical progression and metastatic potential of the disease. Genetic ablation of cJUN and JUNB in this model did not affect tumor incidence, however lymphomas displayed reduced progression, indicated by reduced vascularization as well as a loss of dissemination. This resulted in extended survival; therapeutic inhibition of PDGFRB with the kinase inhibitor markedly prolonged the life of NPM-ALK transgenic mice. We therefore conclude that cJUN/JUNB driven expression of PDGFRB in lymphoma cells induces stromal alterations in the microenvironment of the initial ALCL tumor, which are essential for tumor progression and dissemination. This is pointing towards tumor cell autonomous as well as microenvironmental functions of signaling cascades in ALK driven ALCL. Therefore this mouse model is suitable to study tumor stroma interactions, which are currently lacking. We thus propose to use the CD4- NPM-ALK mouse as a novel model system to study the role of tumor stroma interaction for tumor initiation, progression and dissemination

We plan to analyse the communication between tumor cells and the microenvironment through signaling pathways contributing to tumor progression. The focus of this project will be the investigation of established signaling pathways such as PDGF/PDGFR or CDXL12/CDXR4 in tumor-stroma crosstalk in NPM-ALK lymphomas. To facilitate the project we want to analyse these signaling pathways in NPM-ALK tumor cells by genetic dissection of essential factors in the tumor cells and/or the stromal fibroblasts. This will be achieved in vivo by tumor (via CD4- Cre) or/and stroma specific (via FSP-Cre) and in vitro by the use of the CRISP/Cas9 knockout technology, which will be followed by Xenotransplantation of genetically modified cell- lines. The tumors will be analyzed histologically, cell biologically and at the molecular level.

Abstract: Dissecting PDGFRB function in NPM-ALK driven lymphoma Postdoc Call 2015