beta-Catenin is essential for survival of leukemic stem cells insensitive to kinase inhibition in mice with BCR-ABL-induced chronic myeloid leukemia

Leukemia. 2009 Jan;23(1):109-16. doi: 10.1038/leu.2008.262. Epub 2008 Sep 25.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Benzamides
  • Bone Marrow / pathology
  • Cell Survival / drug effects*
  • Drug Resistance, Neoplasm
  • Imatinib Mesylate
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology*
  • Mice
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / pathology*
  • Piperazines / pharmacology
  • Protein Kinase Inhibitors / pharmacology
  • Pyrimidines / pharmacology
  • Signal Transduction
  • Wnt Proteins
  • beta Catenin / physiology*

Substances

  • Benzamides
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Wnt Proteins
  • beta Catenin
  • Imatinib Mesylate