Theranostics 2016; 6(11):1947-1962. doi:10.7150/thno.16139
Depletion of γ-catenin by Histone Deacetylase Inhibition Confers Elimination of CML Stem Cells in Combination with Imatinib
1. Jinan University Institute of Tumor Pharmacology, Jinan University College of Pharmacy; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China;
2. Laboratory of Medicinal Chemistry, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China;
3. Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China;
4. Department of Hematology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China;
5. Department of Hematology, Guangdong General Hospital/Guangdong Academy of Medical Sciences, Guangzhou, China;
6. Department of Hematology, The First Affiliated Hospital, Jinan University, Guangzhou, China;
7. Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China.
Quiescent leukemia stem cells (LSCs) that are insensitive to BCR-ABL tyrosine kinase inhibitors confer resistance to imatinib in chronic myelogenous leukemia (CML). Identifying proteins to regulate survival and stemness of LSCs is urgently needed. Although histone deacetylase inhibitors (HDACis) can eliminate quiescent LSCs in CML, little is known about the underlying mechanism that HDACis kill LSCs. By fishing with a biotin-labeled probe, we identified that HDACi JSL-1 bound to the protein γ-catenin. γ-Catenin expression was higher in LSCs from CML patients than normal hematopoietic stem cells. Silencing γ-catenin in human CML CD34+ bone-marrow (BM) cells sufficiently eliminated LSCs, which suggests that γ-catenin is required for survival of CML LSCs. Pharmacological inhibition of γ-catenin thwarted survival and self-renewal of human CML CD34+ cells in vitro, and of murine LSCs in BCR-ABL-driven CML mice. γ-Catenin inhibition reduced long-term engraftment of human CML CD34+ cells in NOD.Cg-Prkdcscid II2rgtm1Sug/JicCrl (NOG) mice. Silencing γ-catenin by shRNA in human primary CD34+ cells did not alter β-catenin, implying a β-catenin-independent role of γ-catenin in survival and self-renewal of CML LSCs. Taken together, our findings validate that γ-catenin may be a novel therapeutic target of LSCs, and suppression of γ-catenin by HDACi may explain elimination of CML LSCs.
Keywords: HDAC inhibitor, imatinib-resistance, leukemia stem cells, γ-catenin, BCR-ABL.
Jin Y, Yao Y, Chen L, Zhu X, Jin B, Shen Y, Li J, Du X, Lu Y, Jiang S, Pan J. Depletion of γ-catenin by Histone Deacetylase Inhibition Confers Elimination of CML Stem Cells in Combination with Imatinib. Theranostics 2016; 6(11):1947-1962. doi:10.7150/thno.16139. Available from http://www.thno.org/v06p1947.htm