CLL-283: CLL-Derived Exosomes Turn Endothelial Cells into CLL-Supportive Cells

• Published in: Clinical lymphoma, myeloma and leukemia Vol. 21; pp. S321 - S322
• Main Authors: Rozovski, Uri, Lipshtein, Lian, Sarsor, Zinab, Beery, Einat, Bogen, Shaked, Lahav, Meir, Vitali, Kliminski, Sharan, Roded, Gurevits, Asia, Shimoni, Shai, Raanani, Pia, Uziel, Orit
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.09.2021
• Subjects: CLL; exosomes; lymphoma; CLL; exosomes; lymphoma
• ISSN: 2152-2650; 2152-2669
• DOI: 10.1016/S2152-2650(21)01757-2

We hypothesized that via exosomes, CLL cells turn endothelial cells into “CLL-supportive cells.” To test this hypothesis, we transfected vein-derived (HUVECs) and arterial-derived (HAOEC) endothelial cells with exosomes that we isolated from the peripheral blood of 45 treatment-naïve patients. We found that endothelial cells take up CLL exosomes in a dose- and time-dependent manner. Since CLL cells are protected from apoptosis in an IL-6-rich environment, we wondered whether CLL exosomes turn endothelial cells into IL-6-producing cells. To test this, we exposed endothelial cells to CLL exosomes and found a 50% increase in IL-6 levels, suggesting that the endothelial cells exposed to CLL exosomes produced and secreted IL-6. Subsequently, we filtered out this growth medium and added CLL cells to this IL-6-enriched medium. After 15 minutes, STAT3 became phosphorylated, and there was a 40% decrease in the rate of apoptosis among these cells, indicating that IL-6 activated the STAT3-dependent anti-apoptotic pathway. Phosphor-proteomic analysis of endothelial cells that were loaded with CLL exosomes revealed 23 phosphor-proteins that were upregulated. Annotation analysis unraveled the central role of phosphor-β-catenin. To test whether β-catenin enhances the generation of IL-6 in these cells, we transfected HUVECs with a β-catenin-containing plasmid. We found, by ELISA, a 30% increase in the levels of IL-6 in the culture medium, and, by ChIP, the increased binding of 3 transcription factors (NF-κB, LEF/TCF, and C/EBP) to the IL-6 promoter. Taken together, we found that CLL cells communicate with endothelial cells through the exosomes that they release. Once these exosomes are taken up by endothelia, they turn them into IL-6-producing cells.