Figure 5.

Novel approaches of targeting signaling pathways in leukemia. (a) Effects of indomethacin on CML-LSC. β-Catenin is essential in CMC LSCs that are resistant to imatinib, and treatment with indomethacin inhibits β-catenin and sensitizes the CML LSCs to imatinib. In contrast, in bulk CML β-catenin in not essential and cells are addicted to BCR-ABL and sensitive to BCR-ABL inhibitor imatinib. (b) Recently, it has been discovered that the activity of SIRT1, a NAD-dependent deacetylase, is increased in CML LSCs that are resistant to imatinib, whereas decreased levels are detected in bulk CMCs that are sensitive to imatinib. Also it has been shown that upon treatment of CML-LSC with Tenovin-6, a small-molecule activator of p53, p53 was acetylated and there was increased p53 activity and the CML LSCs became sensitive to imatinib. (c) The CaMKII pathway has been shown to be important in the regulation of β-catenin in imatinib-resistant CML LSCs. Treatment of CML LSCs with the natural product berbamine resulted in CaMKII and β-catenin inhibition and death of the CML LSCs. (d) Berbamine is also effective in inhibiting the growth of bulk CMLs containing the T315I-BCR-ABL mutation in part by inhibiting CaMKII, NF-κB, β-catenin and STAT signaling pathways. (e) The combination of BCR-ABL and GSK-3 inhibitors has been shown to induce a pro-differentiation/apoptotic pathway in CML LSCs. (f) Indomethacin is also effective in inhibiting AML LICs and AML LSCs that are c-Kit high and dependent on β-catenin signaling. This figure is included to provide the reader some of the novel approaches to successfully target CML LSCs and AML LICs and the importance of β-catenin in the survival of both CML LSCs and AML LICs.