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CML as a Human Model in Mice

BCR-ABL-transduced human cord blood cells produce abnormal populations in immunodeficient mice

Leukemia volume 19, pages 442–448 (2005)Cite this article

Abstract

In this study, we describe the successful use of a gene transfer approach to demonstrate the ability of forced BCR-ABL expression to deregulate the growth and differentiation of primitive naïve human hematopoietic cells after their transplantation into immunodeficient mice. Human CD34+ cord blood cells were exposed to an MSCV retrovirus containing a BCR-ABL-IRES-GFP (P210) cassette and then injected immediately into sublethally irradiated nonobese diabetic-severe combined immunodeficiency (NOD/SCID) or NOD/SCID-β2microglobulin−/− mice. P210- and control-transduced (GFP+) human hematopoietic cells were produced in the bone marrow of the mice at similar levels until termination of the experiments 5–6 months later. However, the P210-transduced cells produced a markedly different spectrum of progeny, with an increased ratio of myeloid to B-lymphoid cells and a frequently prolonged increase in erythroid and megakaryocytic cells. After 5 months, several of the mice transplanted with P210-transduced cells developed an increased WBC count and/or splenomegaly due to an expansion of the human GFP+ population. These findings demonstrate that forced expression of BCR-ABL in primitive transplantable human hematopoietic cells is sufficient to cause a rapid and persistent deregulation of their growth and differentiation in vivo with occasional evidence after several months of progression to an early stage of disease.

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Acknowledgements

We thank the staff of the Stem Cell Assay Service and the Flow Cytometry Facility of the Terry Fox Laboratory for initial cell processing and sorting, Dianne Reid for technical assistance, J Griffin (Dana Farber Cancer Institute, Boston, MA, USA) for the BCR-ABL plasmid, K Humphries and P Lansdorp (both from the Terry Fox Laboratory) for the MIG vector and antibodies, and StemCell (Vancouver, BC, Canada), Novartis (Basel, Switzerland), Cangene (Mississauga, ON, Canada) and Immunex (Seattle, WA, USA) for gifts of recombinant growth factors and other reagents. This work was supported by grants from the Cancer Research Society and the Leukemia Research Fund of Canada (XJ), the National Cancer Institute of Canada (with funds from the Canadian Cancer Society) and Genome BC (AE and CE). Y Chalandon was supported by a Terwindt Foundation Fellowship and O Christ by a German Research Foundation Fellowship.

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Author notes

  1. Y Chalandon

    Present address: Hematology Division, University Hospital of Geneva, Geneva, Switzerland

Authors and Affiliations

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

    Y Chalandon, X Jiang, O Christ, S Loutet, E Thanopoulou, A Eaves & C Eaves

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

    A Eaves & C Eaves

  3. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada

    A Eaves & C Eaves

  4. Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada

    C Eaves

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Correspondence to C Eaves.

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Chalandon, Y., Jiang, X., Christ, O. et al. BCR-ABL-transduced human cord blood cells produce abnormal populations in immunodeficient mice. Leukemia 19, 442–448 (2005). https://doi.org/10.1038/sj.leu.2403650

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