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

N. Underhill-Day, A. Pierce, S. E. Thompson, D. Xenaki, A. D. Whetton, P. J. Owen-Lynch

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)774-783
Number of pages10
JournalBritish Journal of Haematology
Volume132
Issue number6
DOIs
Publication statusPublished - 1 Mar 2006
Externally publishedYes

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Drug Resistance
Protein-Tyrosine Kinases
Actins
Myeloid Progenitor Cells
Stem Cells
Leukemia, Myeloid, Chronic Phase
Philadelphia Chromosome
Second Messenger Systems
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Fibronectins
Intercellular Signaling Peptides and Proteins
Cell Line
Temperature
Growth
Proteins

Cite this

Underhill-Day, N. ; Pierce, A. ; Thompson, S. E. ; Xenaki, D. ; Whetton, A. D. ; Owen-Lynch, P. J. / Role of the C-terminal actin binding domain in BCR/ABL-mediated survival and drug resistance. In: British Journal of Haematology. 2006 ; Vol. 132, No. 6. pp. 774-783.
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Role of the C-terminal actin binding domain in BCR/ABL-mediated survival and drug resistance. / Underhill-Day, N.; Pierce, A.; Thompson, S. E.; Xenaki, D.; Whetton, A. D.; Owen-Lynch, P. J.

In: British Journal of Haematology, Vol. 132, No. 6, 01.03.2006, p. 774-783.

Research output: Contribution to journalArticle

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