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Differential effect of leukaemogenic tyrosine kinases on cell motility is governed by subcellular localisation

  1. Andrew Pierce1,
  2. Yuning Lu1,
  3. Hajja G. Hamzah1,
  4. Suzanne Thompson2,
  5. P. J. Owen-Lynch2,
  6. Anthony D. Whetton1,
  7. Elaine Spooncer3

Article first published online: 15 FEB 2006

DOI: 10.1111/j.1365-2141.2006.06015.x

Issue

British Journal of Haematology

British Journal of Haematology

Volume 133, Issue 3, pages 345–352, May 2006

Additional Information

How to Cite

Pierce, A., Lu, Y., Hamzah, H. G., Thompson, S., Owen-Lynch, P. J., Whetton, A. D. and Spooncer, E. (2006), Differential effect of leukaemogenic tyrosine kinases on cell motility is governed by subcellular localisation. British Journal of Haematology, 133: 345–352. doi: 10.1111/j.1365-2141.2006.06015.x

Author Information

  1. 1

    Leukaemia Research Fund Cellular Development Unit, UMIST, Manchester

  2. 2

    Department of Biological Sciences, IENS, University of Lancaster, Bailrigg, Lancaster

  3. 3

    Department of Biomolecular Sciences, UMIST, Manchester, UK

*Anthony D. Whetton, Leukaemia Research Fund Cellular Development Unit, UMIST, PO Box 88, Manchester M60 1QD, UK. E-mail: Tony.Whetton@manchester.ac.uk

Publication History

  1. Issue published online: 31 MAR 2006
  2. Article first published online: 15 FEB 2006
  3. Received 28 November 2005; accepted for publication 10 January 2006

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Keywords:

  • BCR/ABL;
  • TEL/PDGFRβ;
  • stromal cell-derived factor-1;
  • chemotaxis;
  • PI3 kinase;
  • motility

Summary

The chemokine, stromal cell-derived factor-1 (SDF-1) is a crucial regulator of stem cell homing and tethering, and potentiation of this pathway in leukaemias may contribute to the pathogenesis of the disease. A key second messenger in SDF-1 signal/response coupling is phosphatidylinositol 3,4,5-triphosphate [PtdIns(3,4,5)P3]. SDF-1 elevated PtdIns(3,4,5)P3 levels markedly in the multipotent FDCP-mix stem cell line. Similarly, transfection with BCR/ABL or TEL/PDGFRβ leukaemogenic tyrosine kinases chronically elevated PtdIns(3,4,5)P3 levels. However, whilst an SDF-1 chemotactic response was observed in TEL/PDGFRβ-transfected cells, in BCR/ABL cells this was markedly decreased, which was not due to Ras-pathway activation. Thus, multipotent cells can respond to SDF-1, despite chronic increases in this second messenger indicating that a discrete pool of SDF-1-stimulated PtdIns(3,4,5)P3 production drives the chemotactic response. To discern the mechanism for the differential effects of these oncogenes we considered subcellular localisation. As TEL/PDGFRβ has a cytosolic location whilst BCR/ABL associates with actin, we removed the actin-binding domain from BCR/ABL. We observed relocation of BCR/ABL to the cytosol and increased SDF-1 responses. We conclude that the localisation of BCR/ABL to the cytoskeleton is essential for effects on motility and moderating SDF-1 responses is not essential in tyrosine kinase-mediated leukaemic transformation.

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