%0 Journal Article
%T BCR and its mutants, the reciprocal t(9;22)-associated ABL/BCR fusion proteins, differentially regulate the cytoskeleton and cell motility
%A Xiaomin Zheng
%A Saskia G¨¹ller
%A Tim Beissert
%A Elena Puccetti
%A Martin Ruthardt
%J BMC Cancer
%D 2006
%I BioMed Central
%R 10.1186/1471-2407-6-262
%X 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¦Á gradient.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.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.The t(9;22)(q34;q11) is detected in 95% of CML and 20¨C30% of adult ALL. CML is a myeloproliferative syndrome [1]. In contrast, Ph+-ALL is an acute disease characterized by blasts blocked at the pre-lymphatic stage of differentiation. Patients suffering from Ph+-ALL constitute a high risk group of ALL (5¨C10% survival rate after five years)[2]. The factors determining the biological differences between CML and Ph+-ALL are completely unknown.The t(9;22) is a reciprocal translocation. A portion of chromosome 9 translocates onto chromosome 22 (22+), thereby replacing a fragment which in turn translocates onto chromosome 9 (9+) [1]. The derivative of chromosome 22 (22q+) can be revealed by cytogenetic techniques as the so-called Philadelphia chromosome (Ph).On chromosome 22, translocation (9;22) involves the bcr (breakpoint cluster region) locus and there are two principal regions in which the breaks occur: (major) M-bcr, which spans between exons 12 to 16, and (minor) m-bcr, in the first intron, about 50 kb 5' of M-bcr. The product of fusion between M-bcr and abl is a protein of 210 kDa, the p210((BCR-A
%U http://www.biomedcentral.com/1471-2407/6/262