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Chronic Myeloid Leukemia, BCR/ABL Studies and Myeloproliferative Disorders

Lonafarnib reduces the resistance of primitive quiescent CML cells to imatinib mesylate in vitro

Leukemia volume 19, pages 1184–1191 (2005)Cite this article

Abstract

Recent studies indicate that a rare population of primitive quiescent BCR-ABL+ cells are innately insensitive to imatinib mesylate (IM) and persist after IM therapy of patients with chronic myeloid leukemia (CML). New approaches to the eradication of these cells are therefore likely to be crucial to the development of curative therapies for CML. We have now found that Ara-C, LY294002 (a PI-3 (phosphatidylinositol-3′ kinase) kinase inhibitor), 17AAG (a heat-shock protein (HSP)-90 antagonist) and lonafarnib (a farnesyltransfease inhibitor) all enhance the toxicity of IM on K562 cells and on the total CD34+ leukemic cell population from chronic phase CML patients. However, for quiescent CD34+ leukemic cells, this was achieved only by concomitant exposure of the cells to lonafarnib. Ara-C or LY294002 alone blocked the proliferation of these cells but did not kill them, and Ara-C, LY294002 or 17AAG in combination with IM enhanced the cytostatic effect of IM but did not prevent the subsequent regrowth of the surviving leukemic cells. These studies demonstrate the importance of in vitro testing of novel agents on the subset of primary leukemic cells most likely to determine long-term treatment outcomes in vivo.

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Acknowledgements

We wish to thank Allyson Doig and Peter Broadley for technical support. This work was supported by Dr W Robert Bishop, Schering-Plough Research Institute, Kenilworth, New Jersey, Dr Richard Rockefeller, and the National Cancer Institute of Canada with funds from the Terry Fox Run. HGJ is a Kay Kendall Leukemia Fund Fellow; SMG is supported by the Chief Scientist Office and Leukemia Research Fund in UK; and JLG was supported by the Leukemia Research Trust Scotland.

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Authors and Affiliations

  1. ATMU, Section of Experimental Haematology, Department of Medicine and Haematology, Division of Cancer Sciences & Molecular Pathology, University of Glasgow, Glasgow, UK

    H G Jørgensen, S M Graham, J L Godden, J C Mountford & T L Holyoake

  2. SNBTS, Division of Cancer Sciences & Molecular Pathology, University of Glasgow, Glasgow, UK

    E K Allan

  3. Department of Haematology, North Glasgow Hospital University Trust, Glasgow, UK

    L Richmond

  4. Cancer Research UK Formulation Unit, University of Strathclyde, Strathclyde, UK

    M A Elliott

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

    C J Eaves

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Correspondence to T L Holyoake.

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Jørgensen, H., Allan, E., Graham, S. et al. Lonafarnib reduces the resistance of primitive quiescent CML cells to imatinib mesylate in vitro. Leukemia 19, 1184–1191 (2005). https://doi.org/10.1038/sj.leu.2403785

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