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CML as a Human Model in Mice

Different subsets of primary chronic myeloid leukemia stem cells engraft immunodeficient mice and produce a model of the human disease

Leukemia volume 19, pages 435–441 (2005)Cite this article

Abstract

Xenograft models of chronic phase human chronic myeloid leukemia (CML) have been difficult to develop because of the persistence of normal hematopoietic stem cells in most chronic phase CML patients and the lack of methods to selectively isolate the rarer CML stem cells. To circumvent this problem, we first identified nine patients' samples in which the long-term culture-initiating cells were predominantly leukemic and then transplanted cells from these samples into sublethally irradiated NOD/SCID and NOD/SCID-β2microglobulin−/− mice. This resulted in the consistent and durable (>5 months) repopulation of both host genotypes with similar numbers of BCR-ABL+/Ph+ cells. The regenerated leukemic cells included an initial, transient population derived from CD34+CD38+ cells as well as more sustained populations derived from CD34+CD38− progenitors, indicative of a hierarchy of transplantable leukemic cells. Analysis of the phenotypes produced revealed a reduced output of B-lineage cells, enhanced myelopoiesis with excessive production of erythroid and megakaropoietic cells and the generation of primitive (CD34+) leukemic cells displaying an autocrine IL-3 and G-CSF phenotype, all characteristics of primary CML cells. These findings demonstrate the validity of this xenograft model of chronic phase human CML, which should enable future investigation of disease pathogenesis and new approaches to therapy.

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Acknowledgements

We are grateful to colleagues in Bangkok, Thailand; Columbus, OH; Glasgow, Scotland; Houston, TX; Innsbruck, Austria and Vancouver, BC who contributed the patient samples used, the staff of the Stem Cell Assay and FACS facility of the Terry Fox Laboratory for technical assistance, Dr N Heisterkamp (Childrens Hospital, Los Angeles, CA) for the BCR probe, Dr J Dick (Hospital for Sick Children, Toronto, Ontario, Canada) for the P17H8 probe and Dr P Lansdorp (Terry Fox Laboratory) and StemCell Technologies (Vancouver, BC, Canada) for antibodies and culture reagents. The secretarial help of Adrienne Wanhill is also acknowledged. This work was supported by grants from the Cancer Research Society and the Leukemia Research Fund of Canada (to XJ) and the National Cancer Institute of Canada with funds from the Canadian Cancer Society (to AE and CE). W Eisterer was supported by a grant from the Fonds zur Foderung der Wissenschaftlichen Forschung (J17777-MED), O Christ by a German Research Foundation Fellowship and H Glimm by funds from the Mildred Scheel Stiftung fur Krebsforschung, Bonn, Germany and the Verein zur Foerderung der Leukaemie und Tumorforschung, Freiburg, Germany.

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Author notes

  1. W Eisterer and X Jiang: These two authors contributed equally to this work

Authors and Affiliations

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

    W Eisterer, X Jiang, O Christ, H Glimm, K H Lee, E Pang, K Lambie, G Shaw, C J Eaves & A C Eaves

  2. Universitätsklinik für Innere Medizin, Abteilung für Allgemeine Innere Medizin, Innsbruck, Austria

    W Eisterer

  3. Medizinische Abteilung I, Universität Freiburg, Freiburg, Germany

    H Glimm

  4. ATMU, Glasgow University, Glasgow, UK

    T L Holyoake

  5. Universitätsklinik für Innere Medizin, Abteilung für Hämatologie und Onkologie, Innsbruck, Austria

    A L Petzer

  6. Mahidol University, Bangkok, Thailand

    C Auewarakul

  7. University of British Columbia, Vancouver, BC, Canada

    M J Barnett, C J Eaves & A C Eaves

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  1. W Eisterer
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Correspondence to A C Eaves.

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Eisterer, W., Jiang, X., Christ, O. et al. Different subsets of primary chronic myeloid leukemia stem cells engraft immunodeficient mice and produce a model of the human disease. Leukemia 19, 435–441 (2005). https://doi.org/10.1038/sj.leu.2403649

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