| Summary: | Chronic lymphocytic leukaemia (CLL) is characterised by the proliferation of malignant B cells that progressively accumulate into lymphoid tissues and peripheral blood. Whereas CLL cells in the peripheral blood are mainly resting, proliferative and survival signals are provided to CLL cells within the lymphoid tissues in specific structures known as proliferation centres. Understanding the molecular basis for CLL cell migration and retention within lymphoid tissues is therefore essential to devise new treatment strategies for CLL. Expression of the surface molecule CD38 on CLL cells is a marker of poor prognosis. CD38 is a transmembrane ectoenzyme involved in Ca2+ mobilization, and although CD38 expression in CLL cells has been linked to cell migration, the underlying molecular mechanisms are unknown. In this study, the role of CD38 in cell motility was investigated using a CD38 stably transfected CLL-derived cell line (MEC1) and primary CLL cell samples with different CD38 expression levels. CD38 expression markedly enhanced MEC1 cell basal migration and chemotaxis towards the chemokine CCL21. Additionally, CD38 expression increased MEC1 cell spreading on VCAM-1 and reduced their ability to crawl on and transmigrate through an endothelial cell monolayer. These results correlated with increased Rap1 GTPase activity observed in cells expressing CD38 compared to control cells, both in resting conditions and after CCL21 stimulation. An important finding was that CD38 expression increased intracellular basal Ca2+ levels in MEC1 cells. Knockdown and localisation studies in CD38-expressing MEC1 cells revealed that RasGRP2, a Ca2+-regulated guanine nucleotide exchange factor for Rap1, may act as a critical signalling molecule in regulating the CD38-dependent migratory phenotype observed. Data obtained with primary CLL samples indicate that a similar mechanism could be responsible for the increased migration linked to CD38 expression in CLL cells. In conclusion, this study reveals a link between CD38 and a RasGRP2-Rap1 signalling axis, which could contribute to our understanding of the role of CD38 in CLL cell motility and disease progression.
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