Two Distinct Co-Culture Systems, Designed to Mimic the Tumor Microenvironment, Induce Remarkably Similar Phenotypic Changes in Primary CLL Cells

There is growing evidence that interactions in the tumour microenvironment promote the survival, proliferation and drug resistance of primary chronic lymphocytic leukaemia (CLL) cells. Furthermore, progressive CLL is frequently associated with lymphadenopathy, pointing to a crucial role for signals emanating from the tissue microenvironment in the accumulation of malignant B-cells. Proliferation of CLL cells appears to be confined to specialized structures called pseudofollicles, which contain a number of cell types including CLL cells, T-cells, vascular endothelial cells and stromal cells. Using two separate model systems designed to mimic this microenvironment, we characterised the phenotypic changes induced in primary CLL cells and assessed both viability and proliferation when compared with corresponding control cultures. In the first model system we co-cultured CLL cells with mouse embryonic fibroblasts transfected with human CD40L supplemented with soluble IL-4. In the second model system we utilised the microvascular endothelial cell line HMEC-1 with and without the addition of stimulated autologous T-cells. Microarray analysis of this cell line confirmed that it expresses high levels of the CD38 ligand CD31 as well as the cytokines IL-2, IL-4, IL-6 and the chemokines CXCL1 and CXCL2. Both model systems resulted in enhanced CLL cell survival when compared to control cultures (P