title: Gas6/AXL Signaling Regulates Self-Renewal of Chronic Myelogenous Leukemia Stem Cells by Stabilizing β-Catenin.
abstract: Purpose:Quiescent leukemia stem cells (LSC) are important resources of resistance and relapse in chronic myelogenous leukemia (CML). Thus, strategies eradicating CML LSCs are required for cure. In this study, we discovered that AXL tyrosine kinase was selectively overexpressed in primary CML CD34+cells. However, the role of AXL and its ligand Gas6 secreted by stromal cells in the regulation of self-renewal capacity of LSCs has not been well investigated.Experimental Design:The function of CML CD34+cells was evaluated by flow cytometer, CFC/replating, long-term culture-initiating cells (LTC-IC), CML mouse model driven by humanBCR-ABLgene and NOD-scid-IL2Rg-/-(NSI) mice.Results:AXL was selectively overexpressed in primary CML CD34+cells.AXLknockdown reduced the survival and self-renewal capacity of human CML CD34+cells. Pharmacologic inhibition of AXL reduced the survival and self-renewal capacity of human CML LSCsin vitroand in long-term grafts in NSI mice. Human CML CD34+cells conscripted bone marrow-derived stromal cells (BMDSC) and primary mesenchymal stem cells (MSC) to secrete Gas6 to form a paracrine loop that promoted self-renewal of LSCs. Suppression of AXL by shRNA and inhibitor prolonged survival of CML mice and reduced the growth of LSCs in mice. Gas6/AXL ligation stabilizes β-catenin in an AKT-dependent fashion in human CML CD34+cells.Conclusions:Our findings improve the understanding of LSC regulation and validate Gas6/AXL as a pair of therapeutic targets to eliminate CML LSCs.Clin Cancer Res; 23(11); 2842-55. ©2016 AACR.
authors.affiliation: Jinan University Institute of Tumor Pharmacology; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Department of Hematology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Danian
authors.initials: D
authors.lastname: Nie
authors.affiliation: Department of Hematology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Hematology, Guangdong General Hospital/Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Du
authors.affiliation: Department of Hematology, The First Affiliated Hospital, Jinan University, Guangzhou, China.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Hematology, The First Affiliated Hospital, Jinan University, Guangzhou, China.
authors.forename: Yangqiu
authors.initials: Y
authors.lastname: Li
authors.affiliation: Jinan University Institute of Tumor Pharmacology; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: Chang
authors.initials: C
authors.lastname: Liu
authors.affiliation: Jinan University Institute of Tumor Pharmacology; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: Jingfeng
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Jinan University Institute of Tumor Pharmacology; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China. panjx2@mail.sysu.edu.cn.|Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors.forename: Jingxuan
authors.initials: J
authors.lastname: Pan
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D000066673:Cell Self Renewal / Q000235:genetics; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate / Q000008:administration & dosage; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000235:genetics*; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D000068877:Imatinib Mesylate; D036341:Intercellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D051176:beta Catenin; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C495270:CTNNB1 protein, human