Submitted August 23, 2007
Accepted January 18, 2008
Loss of Bcl-x in Ph+ B-ALL increases cellular proliferation and does not inhibit leukemogenesis
Jason G Harb, Brenda I Chyla, and Claudia S Huettner*
Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, Wisconsin, United States
Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, United States
* Corresponding author; email: claudia.huettner{at}bcw.edu.
The kinase inhibitors imatinib mesylate and dasatinib are the preferred treatment for Philadelphia chromosome-positive (Ph+) leukemias and they are highly successful in the chronic phase of chronic myeloid leukemia (CML). However, they are not efficient in Ph+ B-cell acute lymphoblastic leukemia (B-ALL). Ph+ leukemia cells are highly resistant to apoptosis and evidence from cell lines and primary cells suggest Bcl-xL as a critical mediator of resistance to apoptosis, but this concept has never been rigorously tested in an animal model. To clarify the role of Bcl-xL in Ph+ B-ALL, we generated two mouse models. In the first model, Ph+B-ALL and loss of Bcl-xL expression are co-induced, in the second model, leukemia is induced with expression of Bcl-xL protein well above the levels found in wild type lymphoblasts. Deletion of Bcl-xL did not inhibit leukemogenesis or affect apoptosis, but increased cellular proliferation. Consistent with this result, overexpression of Bcl-xL led to decreased cellular proliferation. These models reveal an unexpected role for Bcl-xL in cell cycle entry and the proliferation of tumor cells.
