title: Rapamycin inhibits pre-B acute lymphoblastic leukemia cells by downregulating DNA and RNA polymerases.
abstract: Rapamycin has been shown to inhibit the growth of leukemic cells via an unknown mechanism. In our current study, we show that rapamycin activates autophagy in pediatric t(1;19) pre-B acute lymphoblastic leukemia (pre-B ALL) cells and thereby inhibits proliferation and induces growth arrest in these cells. Rapamycin was found to downregulate an extensive array of positive cell cycle regulators, reduce the total DNA and RNA levels, and specifically downregulate the gene transcription of DNA pol δ1 and RNA pol II. Furthermore, we show that both rapamycin and starvation caused a downregulation of the DNA pol δ1 and RNA pol II proteins which was reversed by the autophagy inhibitor 3-MA. Consistent with the results of our autophagic flux analysis, confocal microscopy indicated that both rapamycin and starvation cause the colocalization of DNA pol δ1 and RNA pol II with GFP-LC3 at autophagosomes. This colocalization was blocked by the autophagy inhibitor bafilomycin A1 which inhibits the fusion between autophagosomes and lysosomes. These data suggest that rapamycin inhibits the growth of pediatric t(1;19) pre-B ALL cells through both transcriptional inhibition and autophagic degradation of DNA pol δ1 and RNA pol II.
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Affiliated Children's Hospital, Soochow University School of Medicine, Soochow University, Suzhou 215123, China.
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Affiliated Children's Hospital, Soochow University School of Medicine, Soochow University, Suzhou 215123, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Xu
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Affiliated Children's Hospital, Soochow University School of Medicine, Soochow University, Suzhou 215123, China.
authors.forename: Na
authors.initials: N
authors.lastname: Yuan
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Affiliated Children's Hospital, Soochow University School of Medicine, Soochow University, Suzhou 215123, China.
authors.forename: Yuna
authors.initials: Y
authors.lastname: Niu
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Affiliated Children's Hospital, Soochow University School of Medicine, Soochow University, Suzhou 215123, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Lin
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Affiliated Children's Hospital, Soochow University School of Medicine, Soochow University, Suzhou 215123, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Affiliated Children's Hospital, Soochow University School of Medicine, Soochow University, Suzhou 215123, China.
authors.forename: Jinyang
authors.initials: J
authors.lastname: Cai
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Affiliated Children's Hospital, Soochow University School of Medicine, Soochow University, Suzhou 215123, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Song
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Affiliated Children's Hospital, Soochow University School of Medicine, Soochow University, Suzhou 215123, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Affiliated Children's Hospital, Soochow University School of Medicine, Soochow University, Suzhou 215123, China.
authors.forename: Yixuan
authors.initials: Y
authors.lastname: Fang
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Affiliated Children's Hospital, Soochow University School of Medicine, Soochow University, Suzhou 215123, China.
authors.forename: Wenli
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Affiliated Children's Hospital, Soochow University School of Medicine, Soochow University, Suzhou 215123, China.
authors.forename: Shaoyan
authors.initials: S
authors.lastname: Hu
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Affiliated Children's Hospital, Soochow University School of Medicine, Soochow University, Suzhou 215123, China.
authors.forename: Suning
authors.initials: S
authors.lastname: Chen
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Affiliated Children's Hospital, Soochow University School of Medicine, Soochow University, Suzhou 215123, China. Electronic address: spzhang@suda.edu.cn.
authors.forename: Suping
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Affiliated Children's Hospital, Soochow University School of Medicine, Soochow University, Suzhou 215123, China. Electronic address: jrwang@suda.edu.cn.
authors.forename: Jianrong
authors.initials: J
authors.lastname: Wang
mesh_terms: D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D002453:Cell Cycle / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004258:DNA Polymerase III / Q000037:antagonists & inhibitors* / Q000235:genetics; D015536:Down-Regulation; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology*; D012319:RNA Polymerase II / Q000037:antagonists & inhibitors* / Q000235:genetics; D020123:Sirolimus / Q000494:pharmacology*
chemical_list: C434055:POLD1 protein, human; D012319:RNA Polymerase II; D004258:DNA Polymerase III; D020123:Sirolimus
keywords: Autophagy; DNA and RNA polymerase; Pre-B cell acute lymphoblastic leukemia; Rapamycin