ABSTRACT
A key characteristic of hematopoietic stem cells (HSCs) is the ability to self-renew. Genetic deletion of ß-catenin during fetal HSC development leads to impairment of self-renewal while ß-catenin is dispensable in fully developed adult HSCs. Whether ß-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 ß-catenin after CML initiation does not lead to a significant increase in survival. However, deletion of ß-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 ß-catenin via modulation of prostaglandin signaling. Treatment with the cyclooxygenase inhibitor indomethacin reduces ß-catenin levels and leads to a reduction in LSCs. In conclusion, inhibiting ß-catenin by genetic inactivation or pharmacologic modulation is an effective combination therapy with imatinib and targets CML stem cells.
