PDGFRB function in lymphoma progression

The large cell anaplastic lymphoma (ALCL) is a highly aggressive T-cell non-Hodgkin`s lymphoma, and often associated with a t(2,5) translocation, which leads to activation of the NPM-ALK fusion protein. Our recent studies identified NPM-ALK as an activator of the AP-1 transcription factors (TF) JUNB and cJun. This TF complex activates the molecule PDGFRB on lymphoma cells and promotes tumor progression and metastasis in a NPM-ALK lymphoma mouse model. The genetic loss of cJun and JUNB in this model system has no effect on tumor incidence, however, reduces the spread of the tumor by reduction of the blood vessels in the tumor, resulting in a reduced tumor growth rate and prolonged survival time of the animals. The treatment of tumors with an inhibitor of PDGFRB (imatinib) also results in a significantly reduced tumor growth and prolonged survival rate of NPM-ALK mice. In addition, treatment with imatinib in a therapy-resistant NPM-ALK-positive ALCL patient resulted in a rapid, complete and long-lasting cure to date. Analysis of a large cohort of NPM-ALK ALCL patients shows that PDGFRB expression on ALCL tumors is significantly associated with poor prognosis compared to patients with PDGFRB negative tumors. We conclude that the cJun / JUNB controlled activity of PDGFRB has an important function in the activation of tumor growth and together with increased PDGFRB activity in stromal cells and in the micro-environment of the tumor promotes rapid tumor expansion in the body. This suggests a dual function of PDGFRB pathway: firstly,: it promotes growth of tumor cells, and secondly, it stimulates the PDGFRB expression in stromal cells in ALCL ALK+ tumors. The focus of this project proposal is to investigate the dual function both in the PDGFRB tumor in stromal cells of ALCL. We also want to investigate the tumor-stroma interaction controlled by PDGFRB and its ligand PDGF tumor-stroma interaction in NPM-ALK lymphomas. To make this possible, we will genetically delete the PDGFRB in tumor cells or stromal fibroblasts or both, to study its function in both compartments of these lymphomas. The tumor-specific deletion of PDGFRB is facilitated in mouse models with PDGFRB-specific expression in tumor cells (with CD4-Cre), and stromal cells can be turned off (via FSP-Cre). The impact of the loss of PDGFRB is investigated histologically, cell biologically but also on a molecular level. Our goal is to better understand the contribution of PDGFRB on tumor-stroma interaction in the formation and spread of ALCL. An improved understanding of these effects should lead directly to new diagnostic and therapeutic strategies for NPM-ALK patients.

PR Summary for FWF P 29251-B28: Anaplastic large cell lymphoma (ALCL) is an aggressive lymph node cancer that mainly affects children and adolescents, but it can also affect adults. A recent international study funded by FWF P 29251-B28 and led by Lukas Kenner has now identified a new biomarker and effective therapeutic approach in the form of the protein PDGFR and the downstream signalling pathway STAT3/5. According to the researchers, the inhibition of this axis promises a therapy with significantly improved prospects of success. ALCL originates from immune T cells and is often caused by the protein NPM-ALK. This is a fusion protein of nucleophosmin (NPM) and anaplastic lymphoma kinase (ALK). Targeting this fusion protein is highly effective, but often leads to relapses. The two transcription factors cJUN and JUNB play a central role in the development of ALCL. They are downstream of the protein NPM-ALK and regulate the protein PDGFR. This project has now identified a new biomarker and therapeutic approach with the PDGFR protein. This study describes that the STAT3/5 signalling pathway is downstream of the PDGFR protein and is partly responsible for making these tumours more aggressive. We have found PDGFR to be a new biomarker and consider PDGFR-STAT3/5 signalling to be the central factor in aggressive ALCL tumours. In addition, we believe that inhibiting PDGFR and/or STAT3/5 will massively improve the survival of patients with ALCL. As part of the project, Lukas Kenner not only succeeded in identifying the role of PDGFR in tumour development, but was also able to show that inhibiting the entire signalling pathway is an effective therapeutic strategy for relapsed patients. The results in the mouse model are promising for people suffering from PDGFR-driven ALCL. This signalling pathway acts as a double-edged sword, giving malignant cells a selective advantage that increases their carcinogenic potential, while also providing an alternative route for pharmacological inhibition. Further studies are now needed to learn more about additional kinases and their underlying molecular mechanisms so that better drug combinations can be developed to prevent tumour recurrence.