Title
beta-Catenin is essential for survival of leukemic stem cells insensitive to kinase inhibition in mice with BCR-ABL-induced chronic myeloid leukemia.
PubMed ID
18818703
UMMS Affiliation
Department of Medicine, Division of Hematology/Oncology
Date
1-1-2009
Document Type
Article
Medical Subject Headings
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 Catenin
Disciplines
Life Sciences | Medicine and Health Sciences
Abstract
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.
Rights and Permissions
Citation: Leukemia. 2009 Jan;23(1):109-16. Epub 2008 Sep 25. Link to article on publisher's website