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Role of the C‐terminal actin binding domain in BCR/ABL‐mediated survival and drug resistance
Author(s) -
UnderhillDay N.,
Pierce A.,
Thompson S. E.,
Xenaki D.,
Whetton A. D.,
OwenLynch P. J.
Publication year - 2006
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2005.05949.x
Subject(s) - progenitor cell , biology , abl , tyrosine kinase , philadelphia chromosome , breakpoint cluster region , cancer research , myeloid leukemia , k562 cells , microbiology and biotechnology , stem cell , leukemia , signal transduction , immunology , receptor , chromosomal translocation , biochemistry , gene
Summary 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.