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 language | English |
|---|---|
| Pages (from-to) | 774-783 |
| Number of pages | 10 |
| Journal | British Journal of Haematology |
| Volume | 132 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - 1 Mar 2006 |
| Externally published | Yes |
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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 journal › Article
TY - JOUR
T1 - Role of the C-terminal actin binding domain in BCR/ABL-mediated survival and drug resistance
AU - Underhill-Day, N.
AU - Pierce, A.
AU - Thompson, S. E.
AU - Xenaki, D.
AU - Whetton, A. D.
AU - Owen-Lynch, P. J.
PY - 2006/3/1
Y1 - 2006/3/1
N2 - 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.
AB - 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.
KW - Actin binding domain
KW - BCR/ABL
KW - Chronic myeloid leukaemia
KW - Drug resistance
KW - Progenitor cells
UR - http://www.scopus.com/inward/record.url?scp=33644930842&partnerID=8YFLogxK
U2 - 10.1111/j.1365-2141.2005.05949.x
DO - 10.1111/j.1365-2141.2005.05949.x
M3 - Article
VL - 132
SP - 774
EP - 783
JO - British Journal of Haematology
JF - British Journal of Haematology
SN - 0007-1048
IS - 6
ER -