title: Bafilomycin A1 targets both autophagy and apoptosis pathways in pediatric B-cell acute lymphoblastic leukemia.
abstract: B-cell acute lymphoblastic leukemia is the most common type of pediatric leukemia. Despite improved remission rates, current treatment regimens for pediatric B-cell acute lymphoblastic leukemia are often associated with adverse effects and central nervous system relapse, necessitating more effective and safer agents. Bafilomycin A1 is an inhibitor of vacuolar H(+)-ATPase that is frequently used at high concentration to block late-phase autophagy. Here, we show that bafilomycin A1 at a low concentration (1 nM) effectively and specifically inhibited and killed pediatric B-cell acute lymphoblastic leukemia cells. It targeted both early and late stages of the autophagy pathway by activating mammalian target of rapamycin signaling and by disassociating the Beclin 1-Vps34 complex, as well as by inhibiting the formation of autolysosomes, all of which attenuated functional autophagy. Bafilomycin A1 also targeted mitochondria and induced caspase-independent apoptosis by inducing the translocation of apoptosis-inducing factor from mitochondria to the nucleus. Moreover, bafilomycin A1 induced the binding of Beclin 1 to Bcl-2, which further inhibited autophagy and promoted apoptotic cell death. In primary cells from pediatric patients with B-cell acute lymphoblastic leukemia and a xenograft model, bafilomycin A1 specifically targeted leukemia cells while sparing normal cells. An in vivo mouse toxicity assay confirmed that bafilomycin A1 is safe. Our data thus suggest that bafilomycin A1 is a promising candidate drug for the treatment of pediatric B-cell acute lymphoblastic leukemia.
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou, China.
authors.forename: Na
authors.initials: N
authors.lastname: Yuan
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Song
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou, China.
authors.forename: Suping
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Lin
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Xu
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou, China.
authors.forename: Yixuan
authors.initials: Y
authors.lastname: Fang
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou, China.
authors.forename: Han
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou, China.
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou, China.
authors.forename: Jinyang
authors.initials: J
authors.lastname: Cai
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou, China.
authors.forename: Xinliang
authors.initials: X
authors.lastname: Mao
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou, China.
authors.forename: Wenli
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou, China.
authors.forename: Shaoyan
authors.initials: S
authors.lastname: Hu
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou, China.
authors.forename: Suning
authors.initials: S
authors.lastname: Chen
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou, China jrwang@suda.edu.cn.
authors.forename: Jianrong
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology; D001343:Autophagy / Q000187:drug effects*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D000071186:Beclin-1; D002467:Cell Nucleus / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D002648:Child; D058546:Class III Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D018942:Macrolides / Q000494:pharmacology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C000595707:BCL2 protein, human; C491997:BECN1 protein, human; D000071186:Beclin-1; D004791:Enzyme Inhibitors; D018942:Macrolides; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C040929:bafilomycin A1; D058546:Class III Phosphatidylinositol 3-Kinases