Inhibition of class II phosphoinositide 3-kinase γ expression by p185Bcr–Abl contributes to impaired chemotaxis and aberrant homing of leukemic cells

Abstract

The expression of p185Bcr–Abl in Ba/F3 cells inhibits the chemotactic response of these cells to SDF1α. A mutant p185Bcr–Abl with deletion of amino acids from 176 to 426 (p185Δ176–426) is deficient in suppressing SDF1α-stimulated chemotaxis. Comparison of the gene expression profiles among parental Ba/F3 cells and cells transformed by p185Bcr–Abl and p185Δ176–426 reveals that class II phosphoinositide 3-kinase γ (PI3KC2γ) expression is markedly down-regulated by p185Bcr–Abl but not p185Δ176–426. Furthermore, knockdown of PI3KC2γ expression in p185Δ176–426 cells is sufficient to suppress SDF1α-stimulated chemotaxis and to promote infiltration of these cells into the liver. Together, these studies suggest that inhibition of PI3KC2γ expression may represent a mechanism by which Bcr–Abl suppresses SDF1α-induced chemotaxis and induces abnormal homing of leukemic cells.