Despite the advancement achieved in the treatment of Chronic Lymphocytic Leukemia (CLL), it remains an incurable disease. The current approach to handle CLL patients is “watch and wait” and the treatment starts when the disease is progressing. Therefore, one of the major challenges is to find genes responsible for the progression of the disease and discover the mechanisms that influence the expression of these genes. All relevant events of CLL occur in tissues where leukemic cells can be exposed to (auto) Ag stimulation and/or utilize microenvironment interaction to avoid apoptosis and acquire better growing conditions. We have recently identified several microRNAs deregulated over the progression of the disease. Here we propose to investigate the influence that components of the microenvironment could have on the expression of microRNAs deregulated in CLL cells over the progression of the disease. We will purify CLL cells and the other cellular components from the three compartments in which CLL cells are located, bone marrow, lymphonodes and peripheral blood. We will assess the expression of selected microRNAs in B-cells after cell-cell mediated interaction. These experiments will clarify if stimuli generated from the cellular cross-talk are responsible for the dysregulation of the microRNAs related to the clinical progression, and in which compartment these events could occur. CLL cells will also be stimulated with plasma from patients with CLL at different stage of progression to identify a possible role of the soluble/secreted molecules on the regulation of the expression of those microRNAs. Together, these findings will lead the discovery of novel mechanisms underlaid the progression of the CLL and will provide new therapeutic targets helping the management of patients with CLL.