Inhibition of class II phosphoinositide 3-kinase γ expression by p185^Bcr–Abl contributes to impaired chemotaxis and aberrant homing of leukemic cells

Abstract

The expression of p185^Bcr–Abl in Ba/F3 cells inhibits the chemotactic response of these cells to SDF1α. A mutant p185^Bcr–Abl with deletion of amino acids from 176 to 426 (p185^Δ176–426) is deficient in suppressing SDF1α-stimulated chemotaxis. Comparison of the gene expression profiles among parental Ba/F3 cells and cells transformed by p185^Bcr–Abl and p185^Δ176–426 reveals that class II phosphoinositide 3-kinase γ (PI3KC2γ) expression is markedly down-regulated by p185^Bcr–Abl but not p185^Δ176–426. Furthermore, knockdown of PI3KC2γ expression in p185^Δ176–426 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.

Keywords:

• PI3KC2γ
• p185^Bcr–Abl
• SDF1α
• chemotaxis

Acknowledgements

We thank Drs. Yingzhu Li and Vishakha Kale for assistance in the migration assay, Dr. Bifeng Gao for DNA microarray analysis, and Dr. William C. Gilmore for pathology/histology analysis.

Declaration of Interest:This work was supported in part by a grant from the National Cancer Institute (R01 CA094921; Z.D.), a grant from the When Everyone Survives Foundation (Z.D.), and a grant from the National Institute of Diabetes and Digestive and Kidney Diseases (grant K01 DK067191; Y.T.).