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Chronic Myeloproliferative Neoplasias

Cleavage of BCR–ABL transcripts at the T315I point mutation by DNAzyme promotes apoptotic cell death in imatinib-resistant BCR–ABL leukemic cells

Leukemia volume 27, pages 1650–1658 (2013)Cite this article

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Abstract

The BCR–ABL fusion transcript encodes the BCR–ABL tyrosine kinase (TK), which causes chronic myelogenous leukemia (CML). Although the TK inhibitor imatinib mesylate, which targets the BCR–ABL protein, has been proven to be effective in controlling leukemic growth, imatinib resistance has been observed with disease relapse because of point mutations in the ABL gene that inhibit imatinib efficacy. In this study, we designed oligodeoxyribozymes (DNAzymes) that specifically target and cleave both the junction sequence and the site of the point mutation (T315I), conferring imatinib resistance in BCR–ABL mRNA. DNAzymes significantly induced apoptosis and inhibited proliferation in wild-type and T315I-mutant BCR–ABL-positive cells. Selective cleavage of T315I-mutant ABL mRNA by DNAzyme (T315I Dz) led to cell cycle arrest in G0/G1 phase, with induction of caspase-3/-7 in imatinib-resistant BCR–ABL-positive cells harboring the T315I mutation. Moreover, cotreatment with the DNAzyme targeting the T315I mutation and imatinib resulted in enhanced inhibition of proliferation and induction of apoptosis in T315I leukemic cells as compared with imatinib alone, thereby antagonizing imatinib resistance in CML cells bearing T315I-mutant BCR–ABL. Therefore, cleavage of T315I-mutant ABL mRNA by DNAzyme combined with imatinib treatment may be an alternative approach to overcoming imatinib resistance in leukemic cells.

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Acknowledgements

We thank the Korean Leukemia Cell and Gene Bank for providing the CML samples. This work was supported by the National Research Foundation grants funded by the Korean Government MEST (2011-0016385 and 2012M3A9B2028336).

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  1. J E Kim and S Yoon: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Bioscience and Biotechnology, Konkuk University, Seoul, Republic of Korea

    J E Kim, S Yoon, B-R Choi & D-E Kim

  2. Department of Molecular Biotechnology, WCU Program, Konkuk University, Seoul, Republic of Korea

    K P Kim

  3. Department of Internal Medicine, Konkuk University, Seoul, Republic of Korea

    Y-H Cho

  4. Department of Emergency Medicine, Kyunghee University Hospital at Gangdong, Seoul, Republic of Korea

    W Jung

  5. Division of Hematology, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Republic of Korea

    D-W Kim

  6. Department of Advanced Fermentation Fusion Science and Technology, Kookmin University, Seoul, Republic of Korea

    S Oh

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Kim, J., Yoon, S., Choi, BR. et al. Cleavage of BCR–ABL transcripts at the T315I point mutation by DNAzyme promotes apoptotic cell death in imatinib-resistant BCR–ABL leukemic cells. Leukemia 27, 1650–1658 (2013). https://doi.org/10.1038/leu.2013.60

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