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

• Published in: EBioMedicine Vol. 15; no. C; pp. 24 - 35
• Main Authors: McCaw, Lindsay, Shi, Yonghong, Wang, Guizhi, Li, You-Jun, Spaner, David E.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.02.2017; Elsevier
• Subjects: Cell Line, Tumor; Cholesterol; Chronic lymphocytic leukemia; Cytokines - metabolism; HMGCR; Humans; Hydroxymethylglutaryl CoA Reductases - metabolism; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Janus kinases; Leukemia, Lymphocytic, Chronic, B-Cell - metabolism; Lipid Metabolism - drug effects; Lipoproteins; Lipoproteins, LDL - metabolism; Lymphocytes - metabolism; Lysosomal lipase; Lysosomes - metabolism; Nuclear receptors; Phosphorylation; Research Paper; Ruxolitinib; Signal Transduction - drug effects; STAT3; STAT3 Transcription Factor - metabolism; Vitamin E - metabolism; Ruxolitinib; Lysosomal lipase; Chronic lymphocytic leukemia; Lipoproteins; STAT3; Janus kinases; HMGCR; Nuclear receptors; Cholesterol
• ISSN: 2352-3964; 2352-3964
• DOI: 10.1016/j.ebiom.2016.11.033

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±10.4months. 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. [Display omitted] •Slow-growing CLL cells use lysosomal lipase to break low density lipoproteins (LDLs) into free fatty acids and cholesterol.•LdL degradation products increase survival of proliferating CLL cells.•LDLs decrease oxidative stress and increase plasma membrane cholesterol.•LDLs amplify signaling responses to cytokines but not antigens in proliferating CLL cells.•Rapidly growing CLL cells, acute leukemia cells, and normal lymphocytes do not exhibit this dependence on LDLs.