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

Abstract

Philadelphia chromosome-positive (Ph þ ) 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 þ 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 b-catenin in the Wnt signaling pathway is essential for survival and self-renewal of LSCs, providing a new strategy for targeting these cells.

Tetrandrine citrate eliminates imatinib-resistant chronic myeloid leukemia cells in vitro and in vivo by inhibiting Bcr-Abl/β-catenin axis

“…These results indicate that tetrandrine citrate can also reduce β-catenin protein levels in leukemia cells. These data suggest that anti-leukemia mechanism of tetrandrine citrate is distinct to that of tyrosine kinase inhibitors (Guzman et al, 2005;Hu et al, 2009). …”

“…β-catenin in the Wnt/β-catenin signaling pathway, which is stabilized by the Bcr-Abl protein level (Coluccia et al, 2007), has been linked to the survival and self-renewal of IM-resistant LSCs (Hu et al, 2009). Therefore, we assessed the effect of tetrandrine citrate on the β-catenin protein levels of IM-resistant K562 cells.…”

“…These targets include the β-catenin in the Wnt/β-catenin pathway (Hu et al, 2009), nuclear factor-κB (NF-κB) pathway (Guzman et al, 2005), CD44 (Krause et al, 2006), Hedgehog pathway (Dierks et al, 2008), Alox5 (Chen et al, 2009a), and PTEN (phosphatase and tensin homolog) (McCubrey et al, 2008). The β-catenin in the Wnt/β-catenin signaling pathway is essential for the self-renewal of Bcr-Abl + CML cells (Coluccia et al, 2007) and the survival of LSCs (Hu et al, 2009), and its protein stability is largely dependent on the protein levels of the Bcr-Abl kinase in Ph + CML cells (Coluccia et al, 2007). These data strongly suggest that the Bcr-Abl/β-catenin axis may be an attractive, yet unrealized treatment option.…”

Insights into the stem cells of chronic myeloid leukemia

“…117,[120][121][122][123] Potential new therapeutic targets include several recently identified regulators of CML stem and progenitor self-renewal and proliferation; for example, promyelocytic leukemia protein, b-catenin, various RNA binding proteins and members of the sonic hedgehog pathway. [89][90][91]97,124,125 Another candidate target identified is CXCR4, the chemokine receptor thought to be involved in normal stem cell localization in the marrow and found to promote the survival of quiescent CML progenitors. 126 Another report has suggested that combining histone deacetylase inhibitors (for example, LAQ824) with IM may be more effective in targeting quiescent CML stem cells than IM alone by inhibiting several genes important to the regulation of HSC maintenance and survival.…”

Molecular and cellular bases of chronic myeloid leukemia

“…CD34 + CML stem cells, especially the undivided CD34 + cell population, are shown to be insensitive to the inhibition by imatinib in a cell culture assay (Graham et al, 2002). Similarly, LSCs could not be eradicated by imatinib in CML mice, as the total numbers and percentages of LSCs in bone marrow of imatinib treated mice continued to increase during the treatment, and the insensitivity of LSCs to imatinib is not associated with the development of imatinib-resistant mutations on BCR-ABL (Hu et al, 2009). Together, these results indicate that some unknown pathways contribute to the maintenance of survival and self-renewal of LSCs,…”