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Spotlight on Stem Cells

Elucidating critical mechanisms of deregulated stem cell turnover in the chronic phase of chronic myeloid leukemia

Leukemia volume 16, pages 549–558 (2002)Cite this article

Abstract

Chronic myeloid leukemia (CML) has been studied intensively for many years; yet its treatment remains problematic and its biology remains elusive. In chronic phase, the leukemic clone appears to be maintained by a small number of BCR-ABL-positive hematopoietic stem cells that differentiate normally and amplify slowly. In contrast, as these cells enter the intermediate stages of lineage restriction, their progeny are selectively expanded and generate an enlarged pool of neoplastic progenitors. Recent analyses of purified subsets of primitive CML cells have provided a coherent explanation for this dichotomous behavior of BCR-ABL-positive stem and progenitor cells based on the discovery of an unusual autocrine IL-3/G-CSF mechanism activated in them. This only partially counteracts in vivosignals that maintain normal stem cells in a quiescent state but, when active in CML stem cells, promotes their differentiation in favor of their self-renewal. In more differentiated CML progenitors, the same mechanism has a more potent mitogenic effect which is then extinguished when the cells enter the terminal stages of differentiation. Thus, further expansion of the clone is limited until inevitably additional mutations are acquired that further distort or override the regulatory mechanisms still operative in the chronic phase.

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Acknowledgements

TLH is supported by a Leukemia Research Fund (LRF) Senior Lectureship. MWD is supported by a LRF Clinical Training Fellowship. Much of the work of the authors reported was obtained with support from the Sylvia Aitken Trust, the Scottish National Blood Transfusion service, the National Cancer Institute of Canada (with funds from the Terry Fox Run and the Canadian Cancer Society), as well as the Leukemia Research Fund of Canada.

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  1. Departments of Medicine and Hematology, Glasgow Royal Infirmary, Glasgow, UK

    TL Holyoake & MW Drummond

  2. Terry Fox Laboratory, British Columbia Cancer Agency Vancouver, Canada

    X Jiang, AC Eaves & CJ Eaves

  3. University of British Columbia, Vancouver, Canada

    AC Eaves & CJ Eaves

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  1. TL Holyoake
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Holyoake, T., Jiang, X., Drummond, M. et al. Elucidating critical mechanisms of deregulated stem cell turnover in the chronic phase of chronic myeloid leukemia. Leukemia 16, 549–558 (2002). https://doi.org/10.1038/sj.leu.2402444

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