¹Division of Hematology/Oncology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA

Correspondence: Dr S Li, Department of Medicine, University of Massachusetts Medical School, Lazare Research Building No. 315, 364 Plantation Street, Worcester, MA 01605, USA. E-mail: Shaoguang.Li@umassmed.edu

²Former address: The Jackson Laboratory, Bar Harbor, ME 04609, USA.

Received 13 November 2007; Revised 26 June 2008; Accepted 30 July 2008; Published online 25 September 2008.

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 -catenin in the Wnt signaling pathway is essential for survival and self-renewal of LSCs, providing a new strategy for targeting these cells.