Details

Autor(en) / Beteiligte

• Heidel, Florian H.
• Bullinger, Lars
• Feng, Zhaohui
• Wang, Zhu
• Neff, Tobias A.
• Stein, Lauren
• Kalaitzidis, Demetrios
• Lane, Steven W.
• Armstrong, Scott A.

Titel

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

Ist Teil von

• Cell stem cell, 2012-04, Vol.10 (4), p.412-424

Ort / Verlag

Cambridge, MA: Elsevier Inc

Erscheinungsjahr

2012

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. ► β- catenin is required for the maintenance of CML stem cells ► β-catenin deletion suppresses CML recurrence after imatinib withdrawal ► β-catenin deletion synergizes with imatinib to target CML stem cells ► COX inhibitors reduce β-catenin levels in CML stem cells and are synergistic with imatinib