title: 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±10.4months. 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.
authors.affiliation: Biology Platform, Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada; Department of Nutritional Sciences, University of Toronto, Toronto, ON, Canada.
authors.forename: Lindsay
authors.initials: L
authors.lastname: McCaw
authors.affiliation: Biology Platform, Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada.
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Biology Platform, Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada.
authors.forename: Guizhi
authors.initials: G
authors.lastname: Wang
authors.affiliation: Biology Platform, Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada; Department of Human Anatomy, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, China.
authors.forename: You-Jun
authors.initials: YJ
authors.lastname: Li
authors.affiliation: Biology Platform, Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Medicine, University of Toronto, Toronto, ON M5G 2C4, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2M9, Canada; Sunnybrook Odette Cancer Center, Toronto, ON M4N 3M5, Canada. Electronic address: spanerd@sri.utoronto.ca.
authors.forename: David E
authors.initials: DE
authors.lastname: Spaner
mesh_terms: D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism*; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism*; D050356:Lipid Metabolism / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008214:Lymphocytes / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014810:Vitamin E / Q000378:metabolism
chemical_list: D016207:Cytokines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008077:Lipoproteins, LDL; D050796:STAT3 Transcription Factor; D014810:Vitamin E; D006903:Hydroxymethylglutaryl CoA Reductases
keywords: Cholesterol; Chronic lymphocytic leukemia; HMGCR; Janus kinases; Lipoproteins; Lysosomal lipase; Nuclear receptors; Ruxolitinib; STAT3