title: Depletion of γ-catenin by Histone Deacetylase Inhibition Confers Elimination of CML Stem Cells in Combination with Imatinib.
abstract: 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-Prkdc (scid) II2rg (tm1Sug)/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.
authors: 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;
authors: Yanli
authors: Y
authors: Jin
authors: Laboratory of Medicinal Chemistry, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China;
authors: Yiwu
authors: Y
authors: Yao
authors: Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China;
authors: Li
authors: L
authors: Chen
authors: Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China;
authors: Xiaohui
authors: X
authors: Zhu
authors: 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;
authors: Bei
authors: B
authors: Jin
authors: Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China;
authors: Yingying
authors: Y
authors: Shen
authors: Department of Hematology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China;
authors: Juan
authors: J
authors: Li
authors: Department of Hematology, Guangdong General Hospital/Guangdong Academy of Medical Sciences, Guangzhou, China;
authors: Xin
authors: X
authors: Du
authors: Department of Hematology, The First Affiliated Hospital, Jinan University, Guangzhou, China;
authors: Yuhong
authors: Y
authors: Lu
authors: Laboratory of Medicinal Chemistry, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China;
authors: Sheng
authors: S
authors: Jiang
authors: 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;; Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors: Jingxuan
authors: J
authors: Pan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002470:Cell Survival / Q000187:drug effects; D051180:Desmoplakins / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D064593:Heterografts; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage*; D006801:Humans; D000068877:Imatinib Mesylate / Q000008:administration & dosage*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D051185:gamma Catenin
chemical_list: D000970:Antineoplastic Agents; D051180:Desmoplakins; D056572:Histone Deacetylase Inhibitors; C495292:JUP protein, human; D051185:gamma Catenin; D000068877:Imatinib Mesylate
keywords: BCR-ABL.; HDAC inhibitor; imatinib-resistance; leukemia stem cells; γ-catenin