CLL microenvironment. Tumor cells migrate to tissues attracted by the chemokines CCL19 and CCL21 produced by high endothelial venules, CXCL12 mainly secreted by nurse-like and stromal cells, and the CXCL13 of the FDCs, which interact with the tumor cell receptors CCR7, CXCR4, and CXCR5, respectively. Adhesion molecules (CD49d, CD44, CD62L) and their ligands (VCAM1, extracellular matrix proteins, CD34, among others) facilitate migration and homing of tumor cells. The presence of antigens in these niches may activate BCR signaling. TLRs recognize molecular patterns that activate the NF-κB pathway via interleukin-1 receptor activated kinase (IRAK)1/4 and MYD88, leading to increased secretion of inflammatory cytokines.¹⁶³  This pathway may cooperate with the BCR stimulation, particularly in M-CLL.¹⁶⁴  IL-4 expression by T cells enhances IgM and CD79b expression, particularly in U-CLL, amplifying the BCR signaling.^165,166  Survival and proliferation stimuli are mainly provided by T cells, particularly through CD40L, and nurse-like and stromal cells through CD31, a proliferation-inducing ligand (APRIL), and B-cell activating factor (BAFF). All of these stimuli play an important role protecting tumor cells from drug-induced apoptosis. The downmodulation of CXCR4 on the CLL cells in tissue facilitates their return to the peripheral blood. CLL cells organize this favorable niche by secreting soluble factors, direct contact with surrounding cells, and release of extracellular vesicles that attract and activate stromal cells.