Importance of Crosstalk Between Chronic Lymphocytic Leukemia Cells and the Stromal Microenvironment: Direct Contact, Soluble Factors, and Extracellular Vesicles.

Chronic lymphocytic leukemia (CLL) is caused by the accumulation of malignant B cells due to a defect in apoptosis and the presence of small population of proliferating cells principally in the lymph nodes. The abnormal survival of CLL B cells is explained by a plethora of supportive stimuli produced by the surrounding cells of the microenvironment, including follicular dendritic cells (FDCs), and mesenchymal stromal cells (MSCs). This crosstalk between malignant cells and normal cells can take place directly by cell-to-cell contact (assisted by adhesion molecules such as VLA-4 or CD100), indirectly by soluble factors (chemokines such as CXCL12, CXCL13, or CCL2) interacting with their receptors or by the exchange of material (protein, microRNAs or long non-coding RNAs) via extracellular vesicles. These different communication methods lead to different activation pathways (including BCR and NFκB pathways), gene expression modifications (chemokines, antiapoptotic protein increase, prognostic biomarkers), chemotaxis, homing in lymphoid tissues and survival of leukemic cells. In addition, these interactions are bidirectional, and CLL cells can manipulate the normal surrounding stromal cells in different ways to establish a supportive microenvironment. Here, we review this complex crosstalk between CLL cells and stromal cells, focusing on the different types of interactions, activated pathways, treatment strategies to disrupt this bidirectional communication, and the prognostic impact of these induced modifications.