Low Density Lipoproteins Amplify Cytokine-signaling in Chronic Lymphocytic Leukemia Cells

Abstract

Recent studies suggest there is a high incidence of elevated low-density lipoprotein (LDL) levels in Chronic Lymphocytic Leukemia (CLL) patients and a survival benefit from cholesterol-lowering statin drugs. The mechanisms of these observations and the kinds of patients they apply to are unclear. Using an in vitro model of the pseudofollicles where CLL cells originate, LDLs were found to increase plasma membrane cholesterol, signaling molecules such as tyrosine-phosphorylated STAT3, and activated CLL cell numbers. The signaling effects of LDLs were not seen in normal lymphocytes or glycolytic lymphoma cell-lines but were restored by transduction with the nuclear receptor PPARδ, which mediates metabolic activity in CLL cells. Breakdown of LDLs in lysosomes was required for the amplification effect, which correlated with down-regulation of HMGCR expression and long lymphocyte doubling times (LDTs) of 53.6 ± 10.4 months. Cholesterol content of circulating CLL cells correlated directly with blood LDL levels in a subgroup of patients. These observations suggest LDLs may enhance proliferative responses of CLL cells to inflammatory signals. Prospective clinical trials are needed to confirm the therapeutic potential of lowering LDL concentrations in CLL, particularly in patients with indolent disease in the “watch-and-wait” phase of management.

Lipids and Their Effects in Chronic Lymphocytic Leukemia

“…The therapeutic target of interest for McCaw et al (2017) in their EBioMedicine article is lipid metabolism. It has been appreciated for many years that lipids have importance in CLL progression and outcomes.…”

“…Within this context, McCaw et al (2017) provide a compelling argument for the role of lipids in inducing second messenger signaling in CLL. The authors were intrigued by a recent case-control study in Canada that demonstrated that CLL patients have more dyslipidemia than age-matched controls, and that CLL patients who took HMG-CoA reductase inhibitors (“statins”) had improved survival compared to CLL patients who did not take these medications, which confirmed similar results in smaller CLL cohorts (Chae et al, 2014, Friedman et al, 2010, Mozessohn et al, 2017).…”

“…In their paper, McCaw et al (2017) focus on LDL potentiation of cytokine-induced STAT3 phosphorylation. The authors demonstrate that LDLs are able to increase STAT3 phosphorylation within the context of cytokine stimulation, not BCR cross-linking.…”

“…McCaw et al's work (McCaw et al, 2017) adds important information to the growing knowledge regarding the effect of lipids on CLL cell biology, however numerous unknowns remain. For example, molecular prognostic markers in the CLL patients in these experiments are not fully detailed, LPL levels are unknown, and serum lipid levels are unknown.…”

“…The key messages to take away from the work performed by McCaw et al (2017) is that lipids and lipoproteins appear to contribute to intracellular second messenger signaling in CLL cells. As these findings occur in the context of stimulated CLL cells in vitro , it is not clear whether these results are important for CLL patients themselves.…”