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BCR-ABL regulates death receptor expression for TNF-related apoptosis-inducing ligand (TRAIL) in Philadelphia chromosome-positive leukemia

Oncogene volume 32, pages 1670–1681 (2013)Cite this article

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Abstract

Allogeneic stem cell transplantation (allo-SCT) is a potentially curative therapy for chronic myeloid leukemia and Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia, and the graft-vs-leukemia (GVL) effect can eradicate residual leukemia after allo-SCT. Ph(+) leukemia cells frequently express death-inducing receptors (DR4 and DR5) for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which is one of the cytotoxic ligands expressed on cytotoxic T cells and natural killer cells mediating the GVL effect. Here we demonstrate that imatinib specifically downregulated DR4 and DR5 expression in cell lines and clinical samples of Ph(+) leukemia. Second-generation tyrosine kinase inhibitors (dasatinib and nilotinib) and short hairpin RNA against bcr-abl also downregulated DR4 and DR5 expression in Ph(+) leukemia cells, and transfection of bcr-abl into a Ph(−) leukemia cell line induced DR4 and DR5 expression, which was abrogated by imatinib treatment. Accordingly, Ph(+) leukemia cells that had been pretreated with imatinib showed resistance to the pro-apoptotic activity of recombinant human soluble TRAIL. These observations demonstrate that BCR-ABL is critically involved in the leukemia-specific expression of DR4 and DR5 and in the susceptibility of Ph(+) leukemia to TRAIL-mediated anti-leukemic activity, providing new insight into the mechanisms of the tumor-specific cytotoxic activities of TRAIL.

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Acknowledgements

The authors thank technological supports by Masako Abe. This work was supported in part by research grants from the Ministry of Education, Science and Culture, Japan.

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Author notes

  1. X Zhang

    Present address: 6Current address: Department of Pediatrics, The General Hospital of Ningxia Medical University, Ningxia, China,

Authors and Affiliations

  1. Department of Pediatrics, School of Medicine, University of Yamanashi, Yamanashi, Japan

    I Kuroda, T Inukai, X Zhang, A Nemoto, K Akahane, K Hirose, H Honna-Oshiro, K Goi, K Kagami & K Sugita

  2. Stem Cell Regulation, Center for Molecular Medicine, Jichi Medical School, Tochigi, Japan

    J Kikuchi & Y Furukawa

  3. Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan

    H Yagita

  4. First Department of Internal Medicine, Tokyo Medical University, Tokyo, Japan

    T Tauchi

  5. Department of Internal Medicine, Division of Hematology, Kinki University School of Medicine, Osaka, Japan

    Y Maeda

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Correspondence to T Inukai.

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Kuroda, I., Inukai, T., Zhang, X. et al. BCR-ABL regulates death receptor expression for TNF-related apoptosis-inducing ligand (TRAIL) in Philadelphia chromosome-positive leukemia. Oncogene 32, 1670–1681 (2013). https://doi.org/10.1038/onc.2012.186

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