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

• Published in: Cell stem cell 2012-04, Vol.10 (4), p.412-424
• Main Authors: Heidel, Florian H., Bullinger, Lars, Feng, Zhaohui, Wang, Zhu, Neff, Tobias A., Stein, Lauren, Kalaitzidis, Demetrios, Lane, Steven W., Armstrong, Scott A.
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Antineoplastic Agents - pharmacology; Benzamides; beta Catenin - antagonists & inhibitors; beta Catenin - genetics; Biological and medical sciences; catenin; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; Cyclooxygenase Inhibitors - pharmacology; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Fetuses; Fundamental and applied biological sciences. Psychology; Gene Deletion; Hematologic and hematopoietic diseases; Humans; Imatinib; Imatinib Mesylate; Indomethacin; Indomethacin - pharmacology; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - metabolism; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - therapy; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Mice; Molecular and cellular biology; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Piperazines - pharmacology; Prostaglandin-endoperoxide synthase; Prostaglandins; Prostaglandins - metabolism; Pyrimidines - pharmacology; Stem cells; Synergism
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2012.02.017

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