Loss of Bcl-x in Ph+ B-ALL increases cellular proliferation and does not inhibit leukemogenesis.
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.
Harb
Jason G
JG
BloodCenter of Wisconsin, Blood Research Institute, Milwaukee 53226, USA.
Chyla
Brenda I
BI
Huettner
Claudia S
CS
D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D004195:Disease Models, Animal; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics; D006801:Humans; D015448:Leukemia, B-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010677:Philadelphia Chromosome; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051020:bcl-X Protein / Q000096:biosynthesis* / Q000235:genetics
C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D051020:bcl-X Protein