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Chronic lymphocytic leukemia

PPAR-delta promotes survival of chronic lymphocytic leukemia cells in energetically unfavorable conditions

Leukemia volume 31, pages 1905–1914 (2017)Cite this article

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Abstract

Targeting the mechanisms that allow chronic lymphocytic leukemia (CLL) cells to survive in harsh cancer microenvironments should improve patient outcomes. The nuclear receptor peroxisome proliferator activated receptor delta (PPARδ) sustains other cancers, and in silico analysis showed higher PPARD expression in CLL cells than normal lymphocytes and other hematologic cancers. A direct association was found between PPARδ protein levels in CLL cells and clinical score. Transgenic expression of PPARδ increased the growth and survival of CD5+ Daudi cells and primary CLL cells in stressful conditions including exhausted tissue culture media, low extracellular glucose, hypoxia and exposure to cytotoxic drugs. Glucocorticoids and synthetic PPARδ agonists up-regulated PPARD expression and also protected Daudi and primary CLL cells from metabolic stressors. Survival in low glucose was related to increased antioxidant expression, substrate utilization and mitochondrial performance, and was reversed by genetic deletion and synthetic PPARδ antagonists. These findings suggest PPARδ conditions CLL cells to survive in harsh microenvironmental conditions by reducing oxidative stress and increasing metabolic efficiency. Targeting PPARδ may be beneficial in the treatment of CLL.

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Acknowledgements

This work was supported by CIHR Grant MOP1304, CIHR Grant MOP 110952, the Leukemia and Lymphoma Society of Canada (DES), NSFC (China) Grant 81372456 and the Fund for the 8th group of Fostering Talents in Jilin Province of China JRZX8 (Y-JL) and CIHR MOP 142352 (RAS). LS was supported by the China Scholarship Council (CSC 201506170134). We thank Peppi Prasit (Inception Sciences, San Diego, CA, USA) for providing NXT1511 and David Andrews (University of Toronto) for ABT-199. DG172 was kindly provided by Prof Dr Wibke E Diederich, Center for Tumor Biology and Immunology, Core Facility Medicinal Chemistry, Philipps-Universität Marburg. We thank Dr Liying Zhang for help with biostastistical analyses.

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Authors and Affiliations

  1. Biology Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada

    Y-J Li, L Sun, Y Shi, G Wang, X Wang, C Iorio & D E Spaner

  2. Department of Human Anatomy, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China

    Y-J Li & L Sun

  3. Department of Breast Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China

    X Wang

  4. Department of Immunology, University of Toronto, Toronto, Ontario, Canada

    S E Dunn & D E Spaner

  5. Toronto General Research Institute, Toronto, Ontario, Canada

    S E Dunn

  6. Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada

    R A Screaton

  7. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada

    D E Spaner

  8. Department of Medical Oncology, Sunnybrook Odette Cancer Center, Toronto, Ontario, Canada

    D E Spaner

  9. Department of Medicine, University of Toronto, Toronto, Ontario, Canada

    D E Spaner

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Li, YJ., Sun, L., Shi, Y. et al. PPAR-delta promotes survival of chronic lymphocytic leukemia cells in energetically unfavorable conditions. Leukemia 31, 1905–1914 (2017). https://doi.org/10.1038/leu.2016.395

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