Genetic and pharmacologic inhibition of ?-catenin targets imatinib-resistant leukemia stem cells in CML.

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

SUBMITTER: Heidel FH 

PROVIDER: S-EPMC3339412 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature