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  • Molecular Targets For Therapy (MTT)
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Molecular Targets for Therapy (MTT)

Telomerase is limiting the growth of acute myeloid leukemia cells

Leukemia volume 17, pages 2410–2417 (2003)Cite this article

Abstract

Telomeres play an important role in the proliferation and senescence of normal and malignant cells. To test the role of telomerase in acute myeloid leukemia (AML), we expressed the telomerase reverse transcriptase (hTERT) gene, a dominant-negative hTERT (DN-hTERT) (D868A, D869A) gene, or a gene encoding green fluorescence protein (GFP) in the leukemia cell line K562 and in primary AML cells from different patients, using retroviral vectors. Cells transduced with hTERT exhibited elevated levels of telomerase activity compared to GFP controls, whereas cells expressing DN-hTERT had decreased telomerase activity. K562 populations transduced with DN-hTERT showed reduced clonogenicity, telomere dysfunction and increased numbers of apoptotic cells compared to GFP- or hTERT-transduced cells. Two of four clones transduced with DN-hTERT died after 30 and 53 population doublings, respectively. Transduced AML cells were tested in primary colony-forming unit (CFU) and suspension culture assays. Relative to hTERT- and GFP-transduced controls, AML cells transfected with DN-hTERT produced fewer CFU and showed lower engraftment after transplantation into sublethally irradiated β2-m−/− nonobese diabetic/severe combined immunodeficient mice. We conclude that telomerase is limiting the growth of the leukemic cell line K562 and primary AML progenitor cells. Our data warrant further studies of the therapeutic use of telomerase inhibitors in AML.

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Acknowledgements

This work was supported by Grants AI29524 from the National Institutes of Health and by a grant from the National Cancer Institute of Canada with funds from the Terry Fox Run. AR is funded by a grant from the Deutsche Forschungsgemeinschaft. We thank Dr Robert Weinberg (MIT, Boston, MA, USA) for hTERT cDNA and Dr Lea Harrington (Toronto) for DN-hTERT (D868A, D869A) cDNA. Dr Keith Humphries and Mike Schertzer (Vancouver) are thanked for help with the construction of the retroviral vectors and Irma Vulto for telomere length measurements.

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  1. A Röth

    Present address: Universitätsklinikum Essen, Zentrum für Innere Medizin, Abt. für Hämatologie, Essen, Germany

  2. A Röth and S Vercauteren: The first two authors contributed equally to this work

Authors and Affiliations

  1. Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada

    A Röth, S Vercauteren, H J Sutherland & P M Lansdorp

  2. Department of Medicine, University of British Columbia, Vancouver, BC, Canada

    H J Sutherland & P M Lansdorp

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  4. P M Lansdorp
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Röth, A., Vercauteren, S., Sutherland, H. et al. Telomerase is limiting the growth of acute myeloid leukemia cells. Leukemia 17, 2410–2417 (2003). https://doi.org/10.1038/sj.leu.2403177

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