Chronic Lymphocytic Leukemia (CLL)-Derived Extracellular Vesicles (EVs) Modulate Monocytes to Become CLL-Supportive Cells.

In light of our previous publication, we hypothesized that chronic lymphocytic leukemia (CLL) cells also recruit monocytes to acquire survival advantage. To test this, we treated Buffy coat-driven monocytes with exosomes isolated from the peripheral blood of 45 treatment-naïve patients. The CLL-derived exosomes turned monocytes into IL-6-producing cells as an increase of 13-fold in the IL-6 levels was obtained in the growth medium of the exposed monocytes. Subsequently, we filtered out the monocytes and added CLL cells to this IL-6 enriched medium. As a result, the oncogene STAT3 became phosphorylated, and thus may have provided the cells with a survival advantage. A total of 67 phosphoproteins were upregulated in response to CLL-derived exosomal exposure in the recipient monocytes, with TFIIF being among the top scored proteins in this analysis. Transfection of monocytes with a TFIIF-containing vector increased the levels of IL-6 about 14-fold in the culture medium. Importantly, the CLL-derived exosomes induced the transformation of a portion of the recipient monocytes (45% compared to 30% of the unexposed cells) to become nurse-like fibrocyte cells. Taken together, CLL cells communicate with monocytes through the exosomes that they release. Once they are taken up by monocytes, they turn them into IL-6-producing cells, which provide a survival advantage to the neoplastic cells, creating a vicious circle that promotes disease progression.