title: PPAR-alpha is a therapeutic target for chronic lymphocytic leukemia.
abstract: Chronic lymphocytic leukemia (CLL) cells with aggressive clinical properties express lipoprotein lipase (LPL), which generates activating ligands for the nuclear receptor peroxisome proliferator activated receptor (PPAR)α and allows fatty acids to be used as fuel. However, the role of PPARα in CLL is unclear. PPARα was found to be expressed by circulating CLL cells and highly associated with advanced stage disease. Consistent with this observation, palmitate oxidation rates in circulating CLL cells were similar to more conventional fat-burning cells such as muscle. Transgenic expression of PPARα in CD5(+) Daudi cells increased both their expression of immunosuppressive factors (that is, interleukin (IL)10 and phospho-STAT3) and resistance to metabolic and cytotoxic stressors. In contrast, marked downregulation of PPARα expression accompanied immunogenic death of proliferating CLL cells. The PPARα antagonist MK886 killed circulating CLL cells directly, caused proliferating CLL cells to enter an immunogenic death pathway and cleared CLL xenografts from immunodeficient mice. These results suggest that PPARα is a biological mediator of CLL and MK886 is a clinically relevant agent with activity against CLL.
authors.affiliation: Division of Molecular and Cellular Biology, Sunnybrook Research Institute, Toronto, Ontario, Canada. spanerd@sri.utoronto.ca
authors.forename: D E
authors.initials: DE
authors.lastname: Spaner
authors.forename: E
authors.initials: E
authors.lastname: Lee
authors.forename: Y
authors.initials: Y
authors.lastname: Shi
authors.forename: F
authors.initials: F
authors.lastname: Wen
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.forename: S
authors.initials: S
authors.lastname: Tung
authors.forename: L
authors.initials: L
authors.lastname: McCaw
authors.forename: K
authors.initials: K
authors.lastname: Wong
authors.forename: H
authors.initials: H
authors.lastname: Gary-Gouy
authors.forename: A
authors.initials: A
authors.lastname: Dalloul
authors.forename: R
authors.initials: R
authors.lastname: Ceddia
authors.forename: R
authors.initials: R
authors.lastname: Gorzcynski
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D047493:PPAR alpha / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D002722:Chlorobenzenes
chemical_list: D007211:Indoles; D016753:Interleukin-10; D047493:PPAR alpha; D012333:RNA, Messenger; C060893:MK-886; D002722:Chlorobenzenes