title: β-Arrestin1 promotes the self-renewal of the leukemia-initiating cell-enriched subpopulation in B-lineage acute lymphoblastic leukemia related to DNMT1 activity.
abstract: The self-renewal ability of the leukemia initiating cell-enriched subpopulation is critical for leukemia initiation and maintenance. However, the regulation of leukemia initiating cells for the leukemia progression is poorly understood. In this study, we observed that β-Arrestin1, a multiple-function protein, is elevated in leukemia initiating cells-enriched fraction from B-lineage acute lymphoblastic leukemia patients. The loss of β-Arrestin1 in leukemia initiating cells-enriched fraction attenuates its self-renewal capacity both in vitro and in vivo. Further experiments showed that the mRNA expression level of β-Arrestin1 is negatively correlated with that of PTEN in leukemia initiating cells-enriched fraction. Moreover, DNA methylation of the PTEN promoter region, the activity and expression of DNMTs were enhanced in the leukemia initiating cells-enriched fraction. The inhibition of DNMT1 activity impaired the self-renewal and increased expression of PTEN of leukemia initiating cells-enriched fraction. In addition, depletion of β-Arrestin1 significantly decreased DNMT1 activity and PTEN methylation, and consistently increased PTEN expression in leukemia initiating cells-enriched fraction. Our study reveals a novel function of β-Arrestin1 in the regulation of the self-renewal of leukemia initiating cells-enriched fraction from B-lineage acute lymphoblastic leukemia patients related to DNMT1 activity, indicating that β-Arrestin1 is a potential therapeutic target in B-lineage acute lymphoblastic leukemia.
authors.affiliation: Center for Clinical Molecular Medicine, Children's Hospital, Chongqing Medical University, Chongqing 400014, China; Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Medical University, Chongqing 400014, China; Key Laboratory of Pediatrics in Chongqing, Children's Hospital, Chongqing Medical University, Chongqing 400014, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Shu
authors.affiliation: Center for Clinical Molecular Medicine, Children's Hospital, Chongqing Medical University, Chongqing 400014, China; Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Medical University, Chongqing 400014, China; Key Laboratory of Pediatrics in Chongqing, Children's Hospital, Chongqing Medical University, Chongqing 400014, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Center for Clinical Molecular Medicine, Children's Hospital, Chongqing Medical University, Chongqing 400014, China; Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Medical University, Chongqing 400014, China; Chongqing Stem Cell Therapy Engineering Technical Research Center, Children's Hospital, Chongqing Medical University, Chongqing 400014, China.
authors.forename: Xinkun
authors.initials: X
authors.lastname: Qi
authors.affiliation: Center for Clinical Molecular Medicine, Children's Hospital, Chongqing Medical University, Chongqing 400014, China; Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Medical University, Chongqing 400014, China; Chongqing Stem Cell Therapy Engineering Technical Research Center, Children's Hospital, Chongqing Medical University, Chongqing 400014, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Liu
authors.affiliation: Center for Clinical Molecular Medicine, Children's Hospital, Chongqing Medical University, Chongqing 400014, China; Key Laboratory of Pediatrics in Chongqing, Children's Hospital, Chongqing Medical University, Chongqing 400014, China; Chongqing Stem Cell Therapy Engineering Technical Research Center, Children's Hospital, Chongqing Medical University, Chongqing 400014, China.
authors.forename: Kang
authors.initials: K
authors.lastname: Li
authors.affiliation: Center for Clinical Molecular Medicine, Children's Hospital, Chongqing Medical University, Chongqing 400014, China; Key Laboratory of Pediatrics in Chongqing, Children's Hospital, Chongqing Medical University, Chongqing 400014, China; Chongqing Stem Cell Therapy Engineering Technical Research Center, Children's Hospital, Chongqing Medical University, Chongqing 400014, China.
authors.forename: Junjie
authors.initials: J
authors.lastname: Tan
authors.affiliation: Center for Clinical Molecular Medicine, Children's Hospital, Chongqing Medical University, Chongqing 400014, China; Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Medical University, Chongqing 400014, China; Key Laboratory of Pediatrics in Chongqing, Children's Hospital, Chongqing Medical University, Chongqing 400014, China.
authors.forename: Zhidai
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Center for Clinical Molecular Medicine, Children's Hospital, Chongqing Medical University, Chongqing 400014, China; Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Medical University, Chongqing 400014, China; Department of Hematology, Children's Hospital, Chongqing Medical University, Chongqing 400014, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yu
authors.affiliation: Center for Clinical Molecular Medicine, Children's Hospital, Chongqing Medical University, Chongqing 400014, China; Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Medical University, Chongqing 400014, China; Key Laboratory of Pediatrics in Chongqing, Children's Hospital, Chongqing Medical University, Chongqing 400014, China.
authors.forename: Penghui
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Center for Clinical Molecular Medicine, Children's Hospital, Chongqing Medical University, Chongqing 400014, China; Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Medical University, Chongqing 400014, China; Key Laboratory of Pediatrics in Chongqing, Children's Hospital, Chongqing Medical University, Chongqing 400014, China; Chongqing Stem Cell Therapy Engineering Technical Research Center, Children's Hospital, Chongqing Medical University, Chongqing 400014, China. Electronic address: zoulin74@hotmail.com.
authors.forename: Lin
authors.initials: L
authors.lastname: Zou
mesh_terms: D000293:Adolescent; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D019390:Arrestins / Q000378:metabolism*; D002648:Child; D019175:DNA Methylation; D005260:Female; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; C411744:DMAP1 protein, human; D012097:Repressor Proteins; D000071557:beta-Arrestins; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: B-lineage acute lymphocytic leukemia; DNA methyltransferases; Leukemia initiating cells-enriched fraction; Self-renewal; β-Arrestin1