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 Blood, 1 April 2008, Vol. 111, No. 7, pp. 3760-3769.
Prepublished online as a Blood First Edition Paper on January 23, 2008; DOI 10.1182/blood-2007-08-108803.

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NEOPLASIA

Loss of Bcl-x in Ph+ B-ALL increases cellular proliferation and does not inhibit leukemogenesis

Jason G. Harb1, Brenda I. Chyla1, and Claudia S. Huettner1,2

1 BloodCenter of Wisconsin, Blood Research Institute, Milwaukee; and 2 Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee

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: however, this concept has never been rigorously tested in an animal model. To clarify the role of Bcl-xL in Ph+ B-ALL, we generated 2 mouse models. In the first model, Ph+ B-ALL and loss of Bcl-xL expression are coinduced; 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.


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