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- W4313366147 abstract "Abstract Clonal expansion of B cell chronic lymphocytic leukemia (B-CLL) is linked to mutagenesis and occurs within lymphoid tissues. CpG DNA (ODN-2006) and IL-15, a cytokine found within stromal cells of B-CLL-infiltrated tissues, manifest striking synergy in promoting in vitro growth of B-CLL cells (J Immunol 195:901–923, 2015). Synergy is in part explained by an ODN-induced, NF-kB (p65)-dependent elevation of IL-15Rα and IL-2/15Rβ (CD122) mRNA and protein (J Immunol 201:1570–1585, 2018). Most recently, we examined the downstream consequences of IL-15 signaling through experiments involving intracellular immunofluorescence staining, pharmacologic inhibitors, RT-PCR, and western blotting. Levels of activated pAKTSer473 and pSTAT5Tyr694 were significantly elevated soon after IL-15 exposure to ODN-primed B-CLL cells; furthermore, STAT5 remained activated throughout cycling. Pharmacologic inhibitors of PI-3K or STAT5 blocked IL-15-driven growth, indicating the functional relevance of these pathways. RT-PCR experiments +/− these inhibitors show that IL-15 signaling in B-CLL is characterized by PI-3K & STAT5-dependent rise in cyclin-D2 and repression of two important DNA damage response (DDR) mediators, ATM and TP53BP1, known to dampen growth and facilitate DNA repair. Repression of the latter two proteins was confirmed by western blotting and immunofluorescence studies. We conclude that IL-15 signaling in TLR9-primed B-CLL can provoke a rapid burst in growth via mechanisms resembling those recently described in CD8 T cells. Nonetheless, because dividing B-CLL cells additionally upregulate the mutagenic enzyme, AICDA (Blood 120: 4802–4811, 2012), these simultaneous events may augment B-CLL mutagenesis." @default.
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- W4313366147 date "2019-05-01" @default.
- W4313366147 modified "2023-10-06" @default.
- W4313366147 title "IL-15-driven clonal expansion of TLR9-primed human B-CLL is characterized by activation of AKT and STAT5, downstream elevation of cyclin D2 and repression of DNA damage response mediators, ATM and TP53BP" @default.
- W4313366147 doi "https://doi.org/10.4049/jimmunol.202.supp.182.62" @default.
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