Journal
BMC CANCER
Volume 6, Issue -, Pages -Publisher
BIOMED CENTRAL LTD
DOI: 10.1186/1471-2407-6-262
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Background: The reciprocal (9; 22) translocation fuses the bcr ( breakpoint cluster region) gene on chromosome 22 to the abl (Abelson-leukemia-virus) gene on chromosome 9. Depending on the breakpoint on chromosome 22 ( the Philadelphia chromosome - Ph+) the derivative 9+ encodes either the p40((ABL/BCR)) fusion transcript, detectable in about 65% patients suffering from chronic myeloid leukemia, or the p96((ABL/BCR)) fusion transcript, detectable in 100% of Ph+ acute lymphatic leukemia patients. The ABL/BCRs are N-terminally truncated BCR mutants. The fact that BCR contains Rho-GEF and Rac-GAP functions strongly suggest an important role in cytoskeleton modeling by regulating the activity of Rho-like GTPases, such as Rho, Rac and cdc42. We, therefore, compared the function of the ABL/BCR proteins with that of wild-type BCR. Methods: We investigated the effects of BCR and ABL/BCRs i.) on the activation status of Rho, Rac and cdc42 in GTPase-activation assays; ii.) on the actin cytoskeleton by direct immunofluorescence; and iii) on cell motility by studying migration into a three-dimensional stroma spheroid model, adhesion on an endothelial cell layer under shear stress in a flow chamber model, and chemotaxis and endothelial transmigration in a transwell model with an SDF-1 alpha gradient. Results: Here we show that both ABL/BCRs lost fundamental functional features of BCR regarding the regulation of small Rho-like GTPases with negative consequences on cell motility, in particular on the capacity to adhere to endothelial cells. Conclusion: Our data presented here describe for the first time an analysis of the biological function of the reciprocal t(9; 22) ABL/BCR fusion proteins in comparison to their physiological counterpart BCR.
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