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Growth autonomy and lineage switching in BCR-ABL-transduced human cord blood cells depend on different functional domains of BCR-ABL

Leukemia volume 18, pages 1006–1012 (2004)Cite this article

Abstract

The tyrosine kinase activity of p210BCR-ABL is essential to its leukemogenic potential, but the role of other functional domains in primary human hematopoietic cells has not been previously investigated. Here we show that infection of normal human CD34+ cord blood (CB) cells with a retroviral vector encoding p210BCR-ABL rapidly activates a factor-independent phenotype and autocrine interleukin-3/granulocyte colony-stimulating factor/erythropoietin production in the transduced cells. These changes are characteristic of primitive chronic myeloid leukemic (CML) cells and are important to the leukemogenicity of BCR-ABL-transduced murine hematopoietic stem cells. When BCR-ABL-transduced human CB cells were incubated with imatinib mesylate, an inhibitor of the p210BCR-ABL kinase, or when human CB cells were transduced with a BCR-ABL cDNA lacking the SH2 domain (p210ΔSH2), factor independence was significantly reduced. In contrast, deletion of the SH2 domain had little impact on the p210BCR-ABL kinase-dependent promotion of erythropoietic differentiation also seen immediately following the BCR-ABL transduction of primitive human CB cells, but not in naturally occurring CML. Thus, p210BCR-ABL has distinct biological effects in primary human hematopoietic cells, which variably mimic features of human CML, and activation of these changes can show different dependencies on the integrity of the SH1 and SH2 domains of p210BCR-ABL.

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Acknowledgements

We thank the members of the Stem Cell Assay Service of the Terry Fox Laboratory for initial cell processing, members of the Flow Cytometry Service for cell sorting, R Van Etten (Center for Blood Research, Boston, MA, USA) for the BCR-ABLΔSH2 cDNA, K Humphries and P Lansdorp (both from the Terry Fox Laboratory) for other cDNA probes and antibodies, and StemCell, Novartis, Cangene and Immunex for gifts of recombinant growth factors and other reagents, and R Premji for assistance in manuscript preparation.

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  1. Y Chalandon and X Jiang: Both these authors contributed equally to this work

Authors and Affiliations

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

    Y Chalandon, X Jiang, S Loutet, A C Eaves & C J Eaves

  2. Hematology Division, University Hospital of Geneva, Geneva, Switzerland

    Y Chalandon

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

    A C Eaves & C J Eaves

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

    A C Eaves & C J Eaves

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

    C J Eaves

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  1. Y Chalandon
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Correspondence to C J Eaves.

Additional information

Supported by grants from the National Cancer Institute of Canada with funds from the Canadian Cancer Society and the Terry Fox Run and a grant from Genome BC. Y Chalandon was supported by a Terwindt Foundation Fellowship and S Loutet held a British Columbia Cancer Foundation Summer Studentship

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Chalandon, Y., Jiang, X., Loutet, S. et al. Growth autonomy and lineage switching in BCR-ABL-transduced human cord blood cells depend on different functional domains of BCR-ABL. Leukemia 18, 1006–1012 (2004). https://doi.org/10.1038/sj.leu.2403335

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