Role of the C-terminal actin binding domain in BCR/ABL-mediated survival and drug resistance.

Underhill-Day, N. and Pierce, Andrew and Thompson, Suzanne and Xenaki, D. and Whetton, A. D. and Owen-Lynch, P. Jane (2006) Role of the C-terminal actin binding domain in BCR/ABL-mediated survival and drug resistance. British Journal of Haematology, 132 (6). pp. 774-783. ISSN 0007-1048

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Philadelphia chromosome-positive, chronic myeloid leukaemia (CML) stem and progenitor cells have a survival and growth advantage compared with their normal counterparts. The mechanisms through which the BCR/ABL protein tyrosine kinase (PTK) induces these effects and the important domains within this protein are not fully defined. The F- and G-actin binding region of the BCR/ABL C-terminus may be important in BCR/ABL-mediated events, and we have investigated this by expressing a C-terminus deletion mutant of the temperature-sensitive BCR/ABL PTK, in a haemopoietic progenitor cell line, which models the chronic phase of CML. The truncated BCR/ABL PTK displayed similar levels of PTK activity when compared with wild type and activation of second messenger formation (in the form of sn-1,2-diacylglycerol) remains intact. On fibronectin substrata, localisation of the protein to the periphery of the cell was, however, dependent on the C-terminus of BCR/ABL PTK. Deletion of the C-terminus reversed both BCR/ABL-mediated apoptotic suppression and drug resistance although the progenitor cells did retain a proliferative advantage at low concentrations of growth factor. These results demonstrated that the C-terminal actin-binding domain of BCR/ABL is important for some of BCR/ABL PTK-mediated leukaemogenic effects.

Item Type:
Journal Article
Journal or Publication Title:
British Journal of Haematology
Uncontrolled Keywords:
?? hematologyqh301 biology ??
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Deposited On:
03 Jun 2008 08:57
Last Modified:
15 Jul 2024 11:38