Abstract
The cytokine-signaling inhibitor ruxolitinib causes disease flares of chronic lymphocytic leukemia (CLL). This tumor-promoting activity correlates with its ability to inhibit interleukin (IL)-10 production by CLL B cells that have been activated with IL-2 and the Toll-like receptor 7 (TLR7) agonist resiquimod (called 2S cells) in vitro. In TLR-activated normal human B cells, IL-10 production is regulated by cholesterol biosynthesis and can be inhibited by statins. The goal of this study was to determine if statins affect IL-10 production by 2S cells. Lipophilic statins decreased IL-10 production from 2S CLL cells by inhibiting activation of MYC along with secondary signaling events that amplify and maintain IL10 transcription. IL-10 production was restored when the prenylation defect imposed by statins was corrected by adding geranylgeranyl pyrophosphate. CLL cells activated by ruxolitinib in vivo were enriched with genes associated with prenylation inhibition in TLR-activated human B cells in vitro. These findings suggest IL-10 production by 2S-activated CLL cells is regulated by cholesterol biosynthesis in part through geranylgeranyl pyrophosphate production and substrate prenylation. If IL-10 production in the 2S model constitutes a surrogate test for drug responses in vivo, realization of the potential clinical benefits of statins in CLL may require coadministration of other agents.