Abstract
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.
Highlights
During the last 20 years, the number of reports dealing with the interaction between chronic lymphocytic leukemia (CLL) and the surrounding cells constituting its microenvironment has increased exponentially
We showed that AMD3100, a bicyclam molecule and specific antagonist of the CXCR4 receptor [146], prevents the binding of CXCL12 and results in a decrease in pseudoemperipolesis and an increase in chemosensitivity to different drugs [71]
The release of CCL3 and CCL4 after coculture with nurse-like cells (NLC) [42] or mesenchymal stromal cells (MSC) [114] or after treatment with MCS-derived extracellular vesicles (EVs) [138] is another example showing that the consequences of microenvironmental interactions could be used as prognostic factors, since CCL3 and CCL4 levels in the plasma of Chronic lymphocytic leukemia (CLL) patients are associated with the time from diagnosis to initial therapy [121]
Summary
During the last 20 years, the number of reports dealing with the interaction between chronic lymphocytic leukemia (CLL) and the surrounding cells constituting its microenvironment has increased exponentially. Because of their cytokine secretion, the adhesion molecules they carry, their ability to activate BCR signaling, and their protective effect on the survival of CLL B cells, FDCs represent another important player of the stromal microenvironment, in secondary lymphoid organs.
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