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Role of the TRAIL/APO2-L death receptors in chlorambucil- and fludarabine-induced apoptosis in chronic lymphocytic leukemia

Oncogene volume 22, pages 8356–8369 (2003)Cite this article

Abstract

The standard treatments for chronic lymphocytic leukemia (CLL) include the alkylating agent chlorambucil (CLB) and the nucleoside analog fludarabine (F-ara-AMP, Flu). Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a death receptor ligand that induces apoptosis preferentially in tumors. However, CLL cells seem to be resistant to TRAIL-induced apoptosis. The TRAIL apoptotic signaling pathway has also been implicated in genotoxin-induced apoptosis through upregulation of TRAIL death receptors DR4 and DR5. In the present study, we demonstrate that the treatment of primary CLL cells with CLB or Flu increases the mRNA, protein and cell surface expression levels of DR4 and DR5 in a dose-dependent manner. In contrast to CLL cells, drug treatment fails to increase significantly the expression of DR4 or DR5 in normal lymphocytes. CLL cells are, however, resistant to TRAIL-induced apoptosis compared to B-cell lines. In contrast, combinational treatment using CLB or Flu with TRAIL (100 ng/ml) gave a synergistic apoptotic response. Furthermore, TRAIL is readily detectable on the cell surface of CLL cells, but TRAIL expression fails to increase following drug treatment. Preventing TRAIL from interacting with DR4 and DR5 decreases CLB-induced apoptosis in CLL cells. A similar, but less marked effect is observed with Flu. These findings indicate the involvement of the TRAIL apoptotic pathway in the mechanism of action of chemotherapy, and this mechanism could be utilized to sensitize CLL cells to TRAIL-induced apoptosis.

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Acknowledgements

We thank the Genomic Centre for Cancer Research and Diagnostics for their technical support of this project. The research was supported by a translational research grant from the Leukemia and Lymphoma Society and a grant from Berlex Canada Inc. In addition, a Shaw Communication Fellowship from the Lymphoma Foundation of Canada supported AK's salary. Finally, we also thank the CancerCare Manitoba Foundation for their continuing support of research into chronic lymphocytic leukemia.

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Authors and Affiliations

  1. Manitoba Institute of Cell Biology, 675 McDermot Ave., Winnipeg, R3E 0V9, Manitoba, Canada

    James B Johnston, Albert F Kabore, Jeanna Strutinsky, Xiaojie Hu, James T Paul, Dianne M Kropp, Brenda Kuschak, Asher Begleiter & Spencer B Gibson

  2. Department of Internal Medicine, University of Manitoba, Winnipeg, R3E 0V9, Manitoba, Canada

    James B Johnston & Asher Begleiter

  3. Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, MB, Canada

    Asher Begleiter

  4. Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, R3E 0V9, Manitoba, Canada

    Spencer B Gibson

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Correspondence to Spencer B Gibson.

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Johnston, J., Kabore, A., Strutinsky, J. et al. Role of the TRAIL/APO2-L death receptors in chlorambucil- and fludarabine-induced apoptosis in chronic lymphocytic leukemia. Oncogene 22, 8356–8369 (2003). https://doi.org/10.1038/sj.onc.1207004

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