As the population ages, the incidence of AML with complex cytogenetics continues to increase. These patients have a poor prognosis with 5% percent of patients diagnosed surviving 5 years. New strategies are needed to improve survival in AML patients. 5q deletion is present in 6–10% of cases of AML, and is a common chromosome abnormality in therapy-related AML (t-AML). 5q deletion is associated with haplo-insufficiency of the APC gene in hematopoietic stem cells and progenitors, leading to deregulation of the Wnt pathway and stabilization of beta- catenin (Wang, J Blood 2010). Loss of APC causes rapid exhaustion of hematopoietic stem cells and progenitors in vivo and leads to the accumulation of beta-catenin (Qian, Z et al JEM 2008). Beta-catenin is required for the development of leukemia stem cells in AML, but it is not required for the self-renewal of normal hematopoietic stem cells (Wang, Y et al Science 2010). Development of treatment strategies aimed at blocking the Wnt pathway through suppression of beta-catenin may improve and prolong remission rates.
The UoCM1 cell line maintains the unique characteristics of del(5q) leukemia (Qian et al, PNAS 2002). Western Blot shows that the expression of beta-catenin was higher in UoCM1 cells versus REH and MV4–11 cell lines, which do not have del(5q). To block the activation of Wnt signaling, through suppression of beta-catenin, we treated UoCM1, REH and MV4–11 cells with 100uM indomethacin. The UoCM1 cells showed 30% growth inhibition while REH and MV-4 cells displayed 10% growth inhibition. The down-regulation of beta-catenin in UocM1 is confirmed by Western Blot. Curcumin is a dietary polyphenol existing in Indian spice turmeric. We showed suppression of beta-catenin by curcumin in 293T cells by luciferase assay. Next, we treated UoCM1 and MV4–11 cells with 5uM or 10 uM curcumin. The growth of UoCM1 cells was significantly inhibited by curcumin as compared to MV4–11 cells. Treatment of UoCM1 cells with 10 uM curcumin produced 87% growth inhibition, while the growth inhibition was 29% for MV4–11 cells. 5uM concentrations of curcumin caused 48% growth inhibition in UoCM1 cells versus 16% in the MV4–11 cell line. Western Blot was performed to confirm that beta-catenin is down-regulated by curcumin, in the UoCM1 cell line.
In summary, blockade of the Wnt pathway through inhibition of beta-catenin suppresses cell growth in UoCM1 leukemia cells, with 5q deletion. Suppression of beta-catenin in combination with cytotoxic therapy may provide a novel means of treating leukemia in patients with a 5q deletion that both improves remission rates and prevents relapse.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.