beta-Catenin is essential for survival of leukemic stem cells insensitive to kinase inhibition in mice with BCR-ABL-induced chronic myeloid leukemia.
UMass Chan Affiliations
Department of Medicine, Division of Hematology/OncologyDocument Type
Journal ArticlePublication Date
2009-01-01Keywords
Animals; Bone Marrow; Cell Survival; Drug Resistance, Neoplasm; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mice; Neoplastic Stem Cells; Piperazines; Protein Kinase Inhibitors; Pyrimidines; Signal Transduction; Wnt Proteins; beta CateninLife Sciences
Medicine and Health Sciences
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Show full item recordAbstract
Philadelphia chromosome-positive (Ph(+)) chronic myeloid leukemia (CML) induced by the BCR-ABL oncogene is believed to be developed from leukemic stem cells (LSCs), and we have previously shown in mice that LSCs for CML express the same cell surface markers that are also expressed on normal hematopoietic stem cells (HSCs). Although the inhibition of BCR-ABL kinase activity by imatinib is highly effective in treating human Ph(+) CML in chronic phase, it is difficult to achieve molecular remission of the disease, suggesting that LSCs remain in patients. In this study, we find that following imatinib treatment, LSCs not only remained but also accumulated increasingly in bone marrow of CML mice. This insensitivity of LSCs to imatinib was not because of the lack of BCR-ABL kinase inhibition by imatinib, and proliferating leukemic cells derived from LSCs were still sensitive to growth inhibition by imatinib. These results identify an LSC survival pathway that is not inhibited by imatinib. Furthermore, we show that beta-catenin in the Wnt signaling pathway is essential for survival and self-renewal of LSCs, providing a new strategy for targeting these cells.Source
Leukemia. 2009 Jan;23(1):109-16. Epub 2008 Sep 25. Link to article on publisher's websiteDOI
10.1038/leu.2008.262Permanent Link to this Item
http://hdl.handle.net/20.500.14038/33044PubMed ID
18818703; 18818703Related Resources
Link to article in PubMedae974a485f413a2113503eed53cd6c53
10.1038/leu.2008.262