title: miR-196b directly targets both HOXA9/MEIS1 oncogenes and FAS tumour suppressor in MLL-rearranged leukaemia.
abstract: HOXA9 and MEIS1 have essential oncogenic roles in mixed lineage leukaemia (MLL)-rearranged leukaemia. Here we show that they are direct targets of miRNA-196b, a microRNA (miRNA) located adjacent to and co-expressed with HOXA9, in MLL-rearranged leukaemic cells. Forced expression of miR-196b significantly delays MLL-fusion-mediated leukemogenesis in primary bone marrow transplantation through suppressing Hoxa9/Meis1 expression. However, ectopic expression of miR-196b results in more aggressive leukaemic phenotypes and causes much faster leukemogenesis in secondary transplantation than MLL fusion alone, likely through the further repression of Fas expression, a proapoptotic gene downregulated in MLL-rearranged leukaemia. Overexpression of FAS significantly inhibits leukemogenesis and reverses miR-196b-mediated phenotypes. Targeting Hoxa9/Meis1 and Fas by miR-196b is probably also important for normal haematopoiesis. Thus, our results uncover a previously unappreciated miRNA-regulation mechanism by which a single miRNA may target both oncogenes and tumour suppressors, simultaneously, or, sequentially, in tumourigenesis and normal development per cell differentiation, indicating that miRNA regulation is much more complex than previously thought.
authors.affiliation: Department of Medicine, University of Chicago, Chicago, 60637, Illinois, USA.
authors.forename: Zejuan
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Medicine, University of Chicago, Chicago, 60637, Illinois, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Medicine, University of Chicago, Chicago, 60637, Illinois, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.affiliation: Department of Medicine, University of Chicago, Chicago, 60637, Illinois, USA.|Department of Pharmacology, China Medical University, Shenyang, 110001, Liaoning, China.
authors.forename: Miao
authors.initials: M
authors.lastname: He
authors.affiliation: Department of Medicine, University of Chicago, Chicago, 60637, Illinois, USA.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Medicine, University of Chicago, Chicago, 60637, Illinois, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Arnovitz
authors.affiliation: Department of Medicine, University of Chicago, Chicago, 60637, Illinois, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Medicine, University of Chicago, Chicago, 60637, Illinois, USA.
authors.forename: Chunjiang
authors.initials: C
authors.lastname: He
authors.affiliation: Department of Pathology, University of Chicago, Chicago, 60637, Illinois, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hyjek
authors.affiliation: Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, 60153, Illinois, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Tang Center for Herbal Medicine Research, University of Chicago, Chicago, 60637, Illinois, USA.
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Genetics and Molecular Biology Branch, National Human Genome Research Institute, NIH, Bethesda, 20892, Maryland, USA.
authors.forename: Abdel
authors.initials: A
authors.lastname: Elkahloun
authors.affiliation: Department of Medicine, University of Chicago, Chicago, 60637, Illinois, USA.|Department of Laboratory Medicine, Guangdong No.2 Provincial People's Hospital, Guangzhou, 510317, Guangdong, China.
authors.forename: Donglin
authors.initials: D
authors.lastname: Cao
authors.affiliation: Department of Medicine, University of Chicago, Chicago, 60637, Illinois, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Shen
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, 45229, Ohio, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Wunderlich
authors.affiliation: Institute of Hematology, the First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, 310058, Zhejiang, China.
authors.forename: Yungui
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Medicine, University of Chicago, Chicago, 60637, Illinois, USA.
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Neilly
authors.affiliation: Institute of Hematology, the First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, 310058, Zhejiang, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Jin
authors.affiliation: Department of Pharmacology, China Medical University, Shenyang, 110001, Liaoning, China.
authors.forename: Minjie
authors.initials: M
authors.lastname: Wei
authors.affiliation: Department of Genetics, Yale Stem Cell Center, Yale University, New Haven, 06520, Connecticut, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Hematology, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands.
authors.forename: Peter J M
authors.initials: PJM
authors.lastname: Valk
authors.affiliation: Department of Hematology, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands.
authors.forename: Ruud
authors.initials: R
authors.lastname: Delwel
authors.affiliation: Department of Hematology, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands.
authors.forename: Bob
authors.initials: B
authors.lastname: Lowenberg
authors.affiliation: Department of Medicine, University of Chicago, Chicago, 60637, Illinois, USA.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Le Beau
authors.affiliation: Department of Pathology, University of Chicago, Chicago, 60637, Illinois, USA.
authors.forename: James
authors.initials: J
authors.lastname: Vardiman
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, 45229, Ohio, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Mulloy
authors.affiliation: Department of Medicine, Loyola University Medical Center, Maywood, 60153, Illinois, USA.
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Zeleznik-Le
authors.affiliation: Genetics and Molecular Biology Branch, National Human Genome Research Institute, NIH, Bethesda, 20892, Maryland, USA.
authors.forename: Paul P
authors.initials: PP
authors.lastname: Liu
authors.affiliation: Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, 60153, Illinois, USA.
authors.forename: Jiwang
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Medicine, University of Chicago, Chicago, 60637, Illinois, USA. jchen@medicine.bsd.uchicago.edu.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006410:Hematopoiesis / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000096:biosynthesis / Q000378:metabolism*; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D051788:Myeloid-Lymphoid Leukemia Protein / Q000096:biosynthesis / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D019014:fas Receptor / Q000378:metabolism*
chemical_list: C491901:FAS protein, human; D018398:Homeodomain Proteins; C000616391:MEIS1 protein, human; C542543:MIRN196 microRNA, human; C000616392:Meis1 protein, mouse; D035683:MicroRNAs; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; D019014:fas Receptor; C097899:homeobox protein HOXA9; D051788:Myeloid-Lymphoid Leukemia Protein