Genetic and Pharmacologic Inhibition of
Menée sur un modèle murin, cette étude suggère que l'inhibition de la bêta-caténine, en combinaison avec l'imatinib, a un effet sur les cellules souches de leucémie myéloïde chronique
A key characteristic of hematopoietic stem cells (HSCs) is the ability to self-renew. Genetic deletion of
β
-catenin during fetal HSC development leads to impairment of self-renewal while
β
-catenin is dispensable in fully developed adult HSCs. Whether
β
-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
β
-catenin after CML initiation does not lead to a significant increase in survival. However, deletion of
β
-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
β
-catenin via modulation of prostaglandin signaling. Treatment with the cyclooxygenase inhibitor indomethacin reduces
β
-catenin levels and leads to a reduction in LSCs. In conclusion, inhibiting
β
-catenin by genetic inactivation or pharmacologic modulation is an effective combination therapy with imatinib and targets CML stem cells. º
β
- catenin is required for the maintenance of CML stem cells º
β
-catenin deletion suppresses CML recurrence after imatinib withdrawal º
β
-catenin deletion synergizes with imatinib to target CML stem cells º COX inhibitors reduce
β
-catenin levels in CML stem cells and are synergistic with imatinib
http://linkinghub.elsevier.com/retrieve/pii/S1934590912000768