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Chronic Lymphocytic Leukemia

PPAR-alpha is a therapeutic target for chronic lymphocytic leukemia

Leukemia volume 27, pages 1090–1099 (2013)Cite this article

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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.

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References

  1. Advani RH, Buggy JJ, Sharman JP, Smith SM, Boyd TE, Grant B et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol 2012, e-pub ahead of print 22 October 2012.

  2. Zenz T, Gribben JG, Hallek M, Döhner H, Keating MJ, Stilgenbauer S . Risk categories and refractory CLL in the era of chemoimmunotherapy. Blood 2012; 119: 4101–4107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Rosenwald A, Alizadeh AA, Widhopf G, Simon R, Davis RE, Yu X et al. Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukemia. J Exp Med 2001; 194: 1639–1647.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ruby MA, Goldenson B, Orasanu G, Johnston TP, Plutzky J, Krauss RM . VLDL hydrolysis by LPL activates PPAR-alpha through generation of unbound fatty acids. J Lipid Res 2010; 51: 2275–2281.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB . The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab 2008; 7: 11–20.

    Article  CAS  PubMed  Google Scholar 

  6. Cheong H, Lu C, Lindsten T, Thompson CB . Therapeutic targets in cancer cell metabolism and autophagy. Nat Biotechnol 2012; 30: 671–678.

    Article  CAS  PubMed  Google Scholar 

  7. Samudio I, Harmancey R, Fiegl M, Kantarjian H, Konopleva M, Korchin B et al. Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction. J Clin Invest 2010; 120: 142–156.

    Article  CAS  PubMed  Google Scholar 

  8. Harmon GS, Lam MT, Glass CK . PPARs and lipid ligands in inflammation and metabolism. Chem Rev 2011; 111: 6321–6340.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Bluemn EG, Nelson PS . The androgen/androgen receptor axis in prostate cancer. Curr Opin Oncol 2012; 24: 251–257.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. de Jong EM, van Vlijmen IM, Scholte JC, Buntinx A, Friedman B, Tanaka W et al. Clinical and biochemical effects of an oral leukotriene biosynthesis inhibitor (MK886) in psoriasis. Skin Pharmacol 1991; 4: 278–285.

    Article  CAS  PubMed  Google Scholar 

  11. Kehrer J, Biswal S, La E, Thuillier P, Datta K, Fischer S et al. Inhibition of PPARalpha by MK886. Biochem J 2001; 356: 899–906.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H et al. International workshop on chronic lymphocytic leukemia. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia. Blood 2008; 111: 5446–5456.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Gitelson E, Hammond C, Mena J, Lorenzo M, Buckstein R, Berinstein NL et al. Chronic lymphocytic leukemia-reactive T cells during tumor progression and after oxidized autologous tumor cell vaccines. Clin Can Res 2003; 9: 1656–1665.

    CAS  Google Scholar 

  14. Wong KK, Brenneman F, Chesney A, Spaner DE, Gorczynski RM . Soluble CD200 Is Critical to Engraft Chronic Lymphocytic Leukemia Cells in Immunocompromised Mice. Cancer Res 2012; 72: 4931–4943.

    Article  CAS  PubMed  Google Scholar 

  15. Bain G, King CD, Rewolinski M, Schaab K, Santini AM, Shapiro D et al. Pharmacodynamics and pharmacokinetics of AM103, a novel inhibitor of 5 lipoxygenase-activating protein (FLAP). Clin Pharmacol Ther 2010; 87: 437–444.

    Article  CAS  PubMed  Google Scholar 

  16. Tomic J, White D, Shi Y, Mena J, Hammond C, He L et al. Sensitization of IL-2 signaling through TLR-7 enhances B lymphoma cell immunogenicity. J Immunol 2006; 176: 3830–3839.

    Article  CAS  PubMed  Google Scholar 

  17. Shaha S, Tomic J, Shi Y, Pham T, Mero P, White D et al. Prolonging microtubule dysruption enhances the immunogenicity of CLL cells. Clin Exp Immunol 2009; 158: 186–198.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Pimenta AS, Gaidhu MP, Habib S, So M, Fediuc S, Mirpourian M et al. Prolonged exposure to palmitate impairs fatty acid oxidation despite activation of AMP-activated protein kinase in skeletal muscle cells. J Cell Physiol 2008; 217: 478–485.

    Article  CAS  PubMed  Google Scholar 

  19. Gary-Gouy H, Sainz-Perez A, Marteau JB, Marfaing-Koka A, Delic J, Merle-Beral H et al. Natural phosphorylation of CD5 in CLL B cells and analysis of CD5-regulated genes in a B cell line suggest a role for CD5 in malignant phenotype. J Immunol 2007; 179: 4335–4344.

    Article  CAS  PubMed  Google Scholar 

  20. Gary-Gouy H, Harriague J, Bismuth G, Platzer C, Schmitt C, Dalloul AH . Human CD5 promotes B-cell survival through stimulation of autocrine IL-10 production. Blood 2002; 100: 4537–4543.

    Article  CAS  PubMed  Google Scholar 

  21. Fayad L, Keating MJ, Reuben JM, O'Brien S, Lee BN, Lerner S et al. Interleukin-6 and interleukin-10 levels in CLL: correlation with phenotypic characteristics and outcome. Blood 2001; 97: 256–63.

    Article  CAS  PubMed  Google Scholar 

  22. Bertilaccio MT, Scielzo C, Simonetti G, Ponzoni M, Apollonio B, Fazi C et al. A novel Rag2-/-gammac-/--xenograft model of human CLL. Blood 2010; 115: 1605–1609.

    Article  CAS  PubMed  Google Scholar 

  23. Joly E, Roduit R, Peyot ML, Habinowski SA, Ruderman NB, Witters LA et al. Glucose represses PPARalpha gene expression via AMPK but not via p38 mitogen-activated protein kinase in the pancreatic beta-cell. J Diabetes 2009; 1: 263–272.

    Article  CAS  PubMed  Google Scholar 

  24. Schulze A, Downward J . Flicking the Warburg switch-tyrosine phosphorylation of pyruvate dehydrogenase kinase regulates mitochondrial activity in cancer cells. Mol Cell 2011; 44: 846–848.

    Article  CAS  PubMed  Google Scholar 

  25. Li YJ, Zhao X, Vecchiarelli-Federico LM, Li Y, Datti A, Cheng Y et al. Drug mediated inhibition of Fli-1 for the treatment of leukemia. Blood Cancer J 2012; 2: e54.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Zenz T, Mertens D, Kuppers R, Dohner H, Stilgenbauer S . From pathogenesis to treatment of chronic lymphocytic leukaemia. Nat Rev Cancer 2010; 10: 37–50.

    Article  CAS  PubMed  Google Scholar 

  27. Tomic J, Lichty B, Spaner DE . Aberrant interferon-signaling is associated with aggressive chronic lymphocytic leukemia. Blood 2011; 117: 2668–2680.

    Article  CAS  PubMed  Google Scholar 

  28. Herishanu Y, Pérez-Galán P, Liu D, Biancotto A, Pittaluga S, Vire B et al. The lymph node microenvironment promotes B-cell receptor signaling, NF-kappaB activation, and tumor proliferation in chronic lymphocytic leukemia. Blood 2011; 117: 563–574.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Green DR, Ferguson T, Zitvogel L, Kroemer G . Immunogenic and tolerogenic cell death. Nat Rev Immunol 2009; 9: 353–363.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Sheikh NA, Jones LA . CD54 is a surrogate marker of antigen presenting cell activation. Cancer Immunol Immunother 2008; 57: 1381–1390.

    Article  CAS  PubMed  Google Scholar 

  31. Karam M, Novak L, Cyriac J, Ali A, Nazeer T, Nugent F . Role of fluorine-18 fluoro deoxyglucose positron emission tomography scan in the evaluation and follow-up of patients with low-grade lymphomas. Cancer 2006; 107: 175–183.

    Article  PubMed  Google Scholar 

  32. Lemberger T, Saladin R, Vázquez M, Assimacopoulos F, Staels B, Desvergne B et al. Expression of the peroxisome proliferator-activated receptor alpha gene is stimulated by stress and follows a diurnal rhythm. J Biol Chem 1996; 271: 1764–1769.

    Article  CAS  PubMed  Google Scholar 

  33. Diehl CJ, Barish GD, Downes M, Chou MY, Heinz S, Glass CK et al. Research resource: comparative nuclear receptor atlas: basal and activated peritoneal B-1 and B-2 cells. Mol Endocrinol 2011; 25: 529–545.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Michalek RD, Gerriets VA, Jacobs SR, Macintyre AN, MacIver NJ, Mason EF et al. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J Immunol 2011; 186: 3299–3303.

    Article  CAS  PubMed  Google Scholar 

  35. Harper ME, Antoniou A, Villalobos-Menuey E, Russo A, Trauger R, Vendemelio M et al. Characterization of a novel metabolic strategy used by drug-resistant tumor cells. FASEB J 2002; 16: 1550–1557.

    Article  CAS  PubMed  Google Scholar 

  36. Panigrahy D, Kaipainen A, Huang S, Butterfield C, Barnés C, Fannon M et al. PPARalpha deficiency in inflammatory cells suppresses tumor growth. PLoS One 2007; 2: e260.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by grants from the Canadian Institutes of Health Research (CIHR) (No.190633) and the Leukemia and Lymphoma Society of Canada (to DS). We thank Peppi Prasit (Inception Sciences, San Diego, CA) for MK886, AM103 and pharmacokinetic analyses.

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Authors and Affiliations

  1. Division of Molecular and Cellular Biology, Sunnybrook Research Institute, Toronto, Canada

    D E Spaner, E Lee, Y Shi, F Wen, Y Li, S Tung & L McCaw

  2. Deptartment of Medical Biophysics, University of Toronto, Toronto, Canada

    D E Spaner

  3. Sunnybrook Odette Cancer Center, Toronto, Canada

    D E Spaner

  4. Deptartment of Medicine, University of Toronto, Toronto, Canada

    D E Spaner

  5. Deptartment of Immunology, University of Toronto, Toronto, Canada

    D E Spaner, K Wong & R Gorzcynski

  6. Transplant Research Division, Toronto General Hospital, Toronto, Canada

    K Wong & R Gorzcynski

  7. Inserm IPSIT IFR 141,

    H Gary-Gouy

  8. Université Paris-Sud, Orsay, France

    H Gary-Gouy

  9. Laboratoire de Therapie Cellulaire, Nancy Universite, Nancy, France

    A Dalloul

  10. School of Kinesiology and Health Science, Faculty of Health, York University, Toronto, Canada

    R Ceddia

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  1. D E Spaner
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Correspondence to D E Spaner.

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Spaner, D., Lee, E., Shi, Y. et al. PPAR-alpha is a therapeutic target for chronic lymphocytic leukemia. Leukemia 27, 1090–1099 (2013). https://doi.org/10.1038/leu.2012.329

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