β-Catenin Inhibition Synergizes with Imatinib to Delay CML Recurrence

First-line treatment of patients with chronic myeloid leukemia (CML) with small-molecule inhibitors of BCR–ABL, such as imatinib, results in high remission rates. However, if imatinib treatment is discontinued, most patients will relapse even if they experienced a complete remission due to the presence of a persistent imatinib-resistant leukemic stem cell population. Heidel and colleagues hypothesized that blocking canonical WNT signaling would specifically target CML leukemic stem cells based on the known role of this pathway in normal hematopoietic stem cell self-renewal. Indeed, conditional deletion of the key WNT effector β-catenin in the bone marrow following establishment of CML in mice led to a significant decrease in the leukemic stem cell population, although leukemic organ infiltration and overall survival were not affected. However, when combined with imatinib, inactivation of β-catenin in the bone marrow of mice with CML not only depleted the leukemic stem cell population and synergistically increased overall survival in a serial transplantation assay, but significantly delayed disease recurrence after imatinib withdrawal. Pharmacologic inhibition of prostaglandin-mediated cross activation of β-catenin with the cyclooxygenase-2 (COX-2) inhibitor indomethacin similarly synergized with imatinib to block CML leukemic stem cell self-renewal and prolong survival after serial transplantation. Consistent with these findings, gene expression data from patients with human chronic-phase CML indicated that COX-2 transcript levels were significantly lower in patients who responded to imatinib treatment, and decreased expression of a prostaglandin-related gene signature was correlated with imatinib response. Together, these data suggest that β-catenin inhibition impairs CML leukemic stem cell self-renewal and indicate that indomethacin could potentially synergize with imatinib in the treatment of CML.

Heidel FH, Bullinger L, Feng Z, Wang Z, Neff TA, Stein L, et al. Genetic and pharmacologic inhibition of β-catenin targets imatinib-resistant leukemia stem cells in CML. Cell Stem Cell 2012;10:412–24.