Inhibition of class II phosphoinositide 3-kinase gamma expression by p185(Bcr-Abl) contributes to impaired chemotaxis and aberrant homing of leukemic cells.

The expression of p185(Bcr-Abl) in Ba/F3 cells inhibits the chemotactic response of these cells to SDF1alpha. A mutant p185(Bcr-Abl) with deletion of amino acids from 176 to 426 (p185(Delta176-426)) is deficient in suppressing SDF1alpha-stimulated chemotaxis. Comparison of the gene expression profiles among parental Ba/F3 cells and cells transformed by p185(Bcr-Abl) and p185(Delta176-426) reveals that class II phosphoinositide 3-kinase gamma (PI3KC2gamma) expression is markedly down-regulated by p185(Bcr-Abl) but not p185(Delta176-426). Furthermore, knockdown of PI3KC2gamma expression in p185(Delta176-426) cells is sufficient to suppress SDF1alpha-stimulated chemotaxis and to promote infiltration of these cells into the liver. Together, these studies suggest that inhibition of PI3KC2gamma expression may represent a mechanism by which Bcr-Abl suppresses SDF1alpha-induced chemotaxis and induces abnormal homing of leukemic cells.

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