Article révisé par les pairs
Résumé : Interactions between chronic lymphocytic leukemia B-cells and the bone marrow microenvironment play a major function in the physiopathology of chronic lymphocytic leukemia. Extracellular vesicles, which are composed of exosomes and microparticles, play an important role in cell communication. However, little is known about their role in chronic lymphocytic leukemia/microenvironment interactions. In the present study, extracellular vesicles purified by ultracentrifugation from bone marrow mesenchymal stromal cell cultures were added to chronic lymphocytic leukemia B-cells. After their integration into chronic lymphocytic leukemia B-cells, we observed a decrease of leukemic cell spontaneous apoptosis and an increase of their chemoresistance to several drugs, including fludarabine, ibrutinib, idelalisib and venetoclax after 24h. Spontaneous (p=0.0078) and stromal cell-derived factor 1α-induced migration capacities of chronic lymphocytic leukemia B-cells were also enhanced (p=0.0020). A microarray study highlighted 805 differentially expressed genes between leukemic cells cultured with or without extracellular vesicles. Of these, genes involved in the B-cell receptor pathway such as CCL3/4, EGR1/2/3, and MYC were increased. Interestingly, this signature presents important overlaps with other microenvironment stimuli such as B-cell receptor stimulation, chronic lymphocytic leukemia /nurse-like cells co-culture or those provided by a lymph node microenvironment. Finally, we showed that extracellular vesicles from mesenchymal stromal cells of leukemic patients also rescue leukemic cells from spontaneous or drug-induced apoptosis. However, they induce a higher migration and also a stronger gene modification compared to extracellular vesicle of healthy mesenchymal stromal cells. In conclusion, we show that extracellular vesicles play a crucial role in chronic lymphocytic leukemia B-cells/bone marrow microenvironment communication.

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