Dysregulation of Actin Polymerization in Hematopoietic Cells Transformed by Bcr-Abl

Actin polymerization is a fundamental cellular process that controls cytoskeletal functions such as adhesion, migration, and homing. This dynamic cellular process is spatiotemporally regulated in normal cells but its dysregulation is often observed in tumor cells and is believed to contribute to tumor metastasis. Hematopoietic cells isolated from Bcr-Abl positive leukemia patients exhibit multiple abnormalities in cytoskeletal function. The mechanism associated with these abnormalities is not completely understood. Previously, we showed that the expression of Bcr-Abl in hematopoietic cells induces tyrosine phosphorylation of Ableson interactor (Abi) 1 and ubiquitin dependent degradation of Abi 2. The dysregulation of Abi 1 and Abi 2 requires the SH3 domain and C-terminal proline-rich sequences of Bcr-Abl. Deletion of these sequences in Bcr-Abl not only abrogates Abi-1 tyrosine phosphorylation and Abi-2 degradation but also impairs leukemogenic activity of Bcr-Abl. Notably, the mutant Bcr-Abl with deletion of these sequences failed to induce splenomegaly in a bone marrow transplant mouse model. Because Abi proteins have been shown to function as a key regulator of actin polymerization, we examined the F-actin organization in Ba/F3 cells transformed by wild type Bcr-Abl (p185wt) and a mutant Bcr-Abl defective in signaling to Abi (p185ΔSH3ΔC). Actin polymerization is increased in Ba/F3 cells transformed by either p185wt or p185ΔSH3ΔC, as compared to control Ba/F3 cells. However, the pattern of F-actin organization in these cells appears different. The expression of p185wt induces a localized abnormal F-actin structure which is not observed in control Ba/F3 cells and the Ba/F3 cells transformed by p185ΔSH3ΔC. We have characterized this abnormal F-actin structure and show that it co-localizes with Bcr-Abl. Investigation is now underway to determine whether the Abi/WAVE pathway is involved in Bcr-Abl-induced abnormal F-actin structure. These studies may provide insight into the mechanism by which Bcr-Abl induces cytoskeletal abnormalities in CML cells.