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.
journal_name
Leukemiajournal_title
Leukemiaauthors
Spaner DE,Lee E,Shi Y,Wen F,Li Y,Tung S,McCaw L,Wong K,Gary-Gouy H,Dalloul A,Ceddia R,Gorzcynski Rdoi
10.1038/leu.2012.329subject
Has Abstractpub_date
2013-04-01 00:00:00pages
1090-9issue
5eissn
0887-6924issn
1476-5551pii
leu2012329journal_volume
27pub_type
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