Chronic Lymphocytic Leukemia (CLL) is a malignancy characterized by the clonal expansion of B cells in blood, bone marrow, and lymphoid tissues. In recent years, the microenvironment has emerged as a crucial contributor to the pathogenesis of CLL. Presently, is clear that tumor progression and/or refractoriness to the therapy is supported by cell-cell interactions and/or soluble molecules signaling which finally trigger on/off different activation pathways involved in tumor progression. Our first work in this area in CLL allow us to identify in the serum of progressive patients the existence of exosomes carrying the pro-inflammatory protein S100A9, which was mostly absent in the exosomes of the indolent patients, (Prieto and Sotelo etn al., Blood, 2017). In this work, our group identified for the first time an undescribed pathway in CLL which could be involved in tumor progression. The work highlights the role of S100A9/EMMPRIN axis during disease progression and hypothesizes that it may become a new therapeutic target in CLL. Our results show that in-vitro stimulation of primary CLL cells with recombinant S100A9 protein increase the phosphorylation of AKT and IKK molecules, suggesting activation of the PI3K/AKT and NF-κB signaling pathways, respectively. These results were extended by expression studies at mRNA and protein level of different genes associated with both pathways. In this line, we found that in-vitro stimulation with S100A9 increases Mcl1, Bcl2, pRb-1, CCL3 and CCL4, and decrease of p27. All of these protein changes were previously associated with tumor progression in CLL. Next, we investigated about the putative functional receptors of S100A9 in CLL cells. Our results showed that B-CLL cells have high expression of EMMPRIN and RAGE receptors and very low expression of TLR4. Very interesting, we found that the EMMPRIN receptor is overexpressed in B-CLL cells of pregressive cases compared to the indolent counterpart . In addition, we found that EMMPRIN is N-glycosylated, with different glycosylation forms (high and low) associated with distinct clinical outcomes. In particular, a higher proportion of the high glycosylation form (HG) is associated with a clinical poor outcome suggesting that the receptor in this form could be more capable to induce activation of the proliferative pathways. Additional studies with different glicosylation levels of EMMPRIN in CLL cells could help us to deepen this hypothesis. Next, we assessed EMMPRIN expression after microenvironment stimuli and found an increase in receptor expression after CD40L plus IL4 stimulation, suggesting the involvement of this pathway in EMMPRIN regulation. Finally, inhibition of S100A9/EMMPRIN interaction with Tasquinimod or Paquinimod, specific inhibitors of the S100A9 protein, or with an EMMPRIN-blocking antibody (clon HM109) led in both cases, to a downregulation of the PI3K/AKT and NF-κB pathways in in-vitro studies. These findings shed new light on the biology of CLL and highlight the potential for targeted therapies to disrupt critical microenvironment interactions. Specifically, inhibition of the S100A9/EMMPRIN axis may represent a promising new therapeutic approach for the treatment of CLL.