The Microenvironment as a Target for Therapy in Chronic Lymphocytic Leukemia

One of the hallmarks of malignant cells is the deregulation of their growth, survival and differentiation. In the case of Chronic Lymphocytic Leukemia (CLL), cellular physiology is regulated, to a large extent, by micro environmental elements that operate within the bone marrow and secondary lymphoid tissues. Extracellular cues that are vital for CLL cells survival and proliferation are exerted by interactions of CLL cells with accessory cells such as T-cells, mesenchymal stromal cells, endothelial cells, follicular dendritic cells and macrophages. CLL cells interact directly with effect or cells via a variety of adhesion molecules, while cytokines, chemokines, enzymes and growth factors provide a complex soluble regulatory network. The B-cell receptor (BCR) is the central source of signals that regulate CLL cells physiological responses. These signals can be triggered by the engagement of the receptor by extracellular antigens of either of microbial origin or auto antigens. Alternatively, as has been revealed in the recent years, the BCR can be activated by ligand-independent cell-autonomous signaling mechanisms. Due to its prime importance in CLL physiology, the biochemical array that mediates micro environmental-derived signaling responses in CLL cells became a useful target for the development of novel effective therapeutics. For example, small molecule inhibitors of SYK, BTK, or PI3K6, all participate in BCR signaling responses, have shown remarkable Clinical effects. Also, BCL-2 inhibitors and immune modulatory drugs are being tested in clinical trials in CLL, with encouraging results. Hence, better understanding of CLL cells’ interaction with the microenvironment can continuously provide clinicians with novel effective therapeutics to control CLL.