The Role of the Microenvironment and Cell Adhesion Molecules in Chronic Lymphocytic Leukemia

SIMPLE SUMMARY: Progression of chronic lymphocytic leukemia (CLL) and its response to therapies are largely dependent on the microenvironment of the bone marrow and lymph nodes, which nurtures leukemic cells and protects them from therapeutic agents. Hence, cell trafficking between the blood vessels and lymphatic tissues is critical for CLL pathophysiology. Cell adhesion molecules mediate the re-localization of CLL cells in different anatomical compartments and are involved in their survival and proliferation. Evaluation of the molecular mechanisms underlying their activation and functions has uncovered clinically relevant signaling pathways targeted by well-established and new therapeutic strategies. The aim of this review is to summarize the current knowledge regarding the microenvironment and the cell adhesion molecules that have been shown to be important in CLL and their role in transendothelial migration and cell adhesion-mediated drug resistance. We also discuss how novel therapeutic compounds modulate the functions of this important class of molecules. ABSTRACT: Chronic lymphocytic leukemia (CLL) is a B-cell malignancy whose progression largely depends on the lymph node and bone marrow microenvironment. Indeed, CLL cells actively proliferate in specific regions of these anatomical compartments, known as proliferation centers, while being quiescent in the blood stream. Hence, CLL cell adhesion and migration into these protective niches are critical for CLL pathophysiology. CLL cells are lodged in their microenvironment through a series of molecular interactions that are mediated by cellular adhesion molecules and their counter receptors. The importance of these adhesion molecules in the clinic is demonstrated by the correlation between the expression levels of some of them, in particular CD49d, and the prognostic likelihood. Furthermore, novel therapeutic agents, such as ibrutinib, impair the functions of these adhesion molecules, leading to an egress of CLL cells from the lymph nodes and bone marrow into the circulation together with an inhibition of homing into these survival niches, thereby preventing disease progression. Several adhesion molecules have been shown to participate in CLL adhesion and migration. Their importance also stems from the observation that they are involved in promoting, directly or indirectly, survival signals that sustain CLL proliferation and limit the efficacy of standard and novel chemotherapeutic drugs, a process known as cell adhesion-mediated drug resistance. In this respect, many studies have elucidated the molecular mechanisms underlying cell adhesion-mediated drug resistance, which have highlighted different signaling pathways that may represent potential therapeutic targets. Here, we review the role of the microenvironment and the adhesion molecules that have been shown to be important in CLL and their impact on transendothelial migration and cell-mediated drug resistance. We also discuss how novel therapeutic compounds modulate the function of this important class of molecules.