Cellular interactions in the microenvironment of chronic lymphocytic leukaemia

• Applicant: Dr. Charlotte Schmidt-Hieber
• Subject Area: Hematology, Oncology
• Term: from 2017 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 329053948

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world and currently not curable by conventional therapy. Interaction between CLL cells and bystander cells in lymph nodes and bone marrow is essential for establishment of the disease and leads to chemotherapy resistance. In order to disrupt the support that is sustaining CLL, further research is needed not only on the nature and effects of protective factors released by bystander cells, but also on the manipulation mechanisms used by CLL cells to receive them. One pivotal survival stimulus for the malignant cells is activation of their B cell antigen receptor (BCR) and clinical use of substances blocking BCR downstream signalling has led to impressive therapeutic responses, but not to cure from the disease. Molecular research showed persistent activation of downstream targets under efficient BCR blockade, and a recent study has identified the insulin-like growth factor 1 receptor (IGF1R) as an important candidate for alternative pathway activation. We could show that in fact, dual BCR and IGF1R blockade leads to a synergistic decrease in CLL cell viability in stromal cell co-culture. Since this effect was independent of IGF1R expression in the CLL samples examined, we hypothesise that part of the effect might be due to the impact of IGF1R blockade on co-cultured stromal cells. The aims of the proposed project are to identify the molecular effect of combined BCR and IGF1R blockade in CLL and stromal cells, the mechanisms used by CLL cells to manipulate bystander cells and the functional relevance of cross talk between bystander cells. We will use in vitro co-culture systems with CLL, stromal and monocytic cells and analyse cross talk and signal integration in the respective cell types through gene expression profiling and use of a novel bioinformatic analysis pipeline that has been established in the host laboratory. Complementary protein, phosphorylation and cytokine analysis will be performed for intracellular and soluble factors. To assess the significance of cross talk with CLL and stromal cells for immunological properties of the monocytic cells, we will examine cellular migration in organotypic culture and monocytic surface markers, cytokine secretion, phagocytic function and functional T cell interaction. These experiments may reveal targetable molecular mechanisms for novel therapeutic approaches that may ultimately yield deeper or even complete remissions in CLL patients.

• DFG Programme: Research Fellowships
• International Connection: France
• Host: Dr. Vassili Soumelis