Genetic and Pharmacologic Inhibition of β-Catenin Targets Imatinib-Resistant Leukemia Stem Cells in CML

A key characteristic of hematopoietic stem cells (HSCs) is the ability to self-renew. Genetic deletion of beta-catenin during fetal HSC development leads to impairment of self-renewal while beta-catenin is dispensable in fully developed adult HSCs. Whether beta-catenin is required for maintenance of fully developed CML leukemia stem cells (LSCs) is unknown. Here, we use a conditional mouse model to show that deletion of beta-catenin after CML initiation does not lead to a significant increase in survival. However, deletion of beta-catenin synergizes with imatinib (IM) to delay disease recurrence after imatinib discontinuation and to abrogate CML stem cells. These effects can be mimicked by pharmacologic inhibition of beta-catenin via modulation of prostaglandin signaling. Treatment with the cyclooxygenase inhibitor indomethacin reduces beta-catenin levels and leads to a reduction in LSCs. In conclusion, inhibiting beta-catenin by genetic inactivation or pharmacologic modulation is an effective combination therapy with imatinib and targets CML stem cells.