title: The leukemogenic fusion gene MLL-AF9 alters microRNA expression pattern and inhibits monoblastic differentiation via miR-511 repression.
abstract: BACKGROUND
  In this study we explored the role of microRNAs (miRNAs) as mediators of leukemogenic effects of the fusion gene MLL-AF9, which results from a frequent chromosomal translocation in infant and monoblastic acute myeloid leukemia (AML).
  
  
  METHODS
  We performed a specific and efficient knockdown of endogenous MLL-AF9 in the human monoblastic AML cell line THP1.
  
  
  RESULTS
  The knockdown associated miRNA expression profile revealed 21 MLL-AF9 dependently expressed miRNAs. Gene ontology analyses of target genes suggested an impact of these miRNAs on downstream gene regulation via targeting of transcriptional modulators as well as involvement in many functions important for leukemia maintenance as e.g. myeloid differentiation, cell cycle and stem cell maintenance. Furthermore, we identified one of the most intensely repressed miRNAs, miR-511, to raise CCL2 expression (a chemokine ligand important for immunosurveillance), directly target cyclin D1, inhibit cell cycle progression, increase cellular migration and promote monoblastic differentiation. With these effects, miR-511 may have a therapeutic potential as a pro-differentiation agent as well as in leukemia vaccination approaches.
  
  
  CONCLUSIONS
  Our study provides new insights into the understanding of miRNAs as functional mediators of the leukemogenic fusion gene MLL-AF9 and opens new opportunities to further investigate specific therapeutic options for AML via the miRNA level.
authors.affiliation: Division of Pediatric Hematology and Oncology, Children's Research Center, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität München, Lindwurmstrasse 2a, 80337, Munich, Germany. katrin.fleischmann@med.uni-muenchen.de.
authors.forename: Katrin K
authors.initials: KK
authors.lastname: Fleischmann
authors.affiliation: Lehrstuhl für Genomorientierte Bioinformatik, Technische Universität München, Maximus-von-Imhof-Forum 3, 85354, Freising, Germany. philipp.pagel@t-online.de.
authors.forename: Philipp
authors.initials: P
authors.lastname: Pagel
authors.affiliation: Division of Pediatric Hematology and Oncology, Children's Research Center, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität München, Lindwurmstrasse 2a, 80337, Munich, Germany. Julia.Frowein@med.uni-muenchen.de.
authors.forename: Julia
authors.initials: J
authors.lastname: von Frowein
authors.affiliation: Division of Pediatric Hematology and Oncology, Children's Research Center, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität München, Lindwurmstrasse 2a, 80337, Munich, Germany. Thomas.Magg@med.uni-muenchen.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Magg
authors.affiliation: Children's Research Center, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität München, Lindwurmstrasse 2a, 80337, Munich, Germany. Adelbert.Roscher@med.uni-muenchen.de.
authors.forename: Adelbert A
authors.initials: AA
authors.lastname: Roscher
authors.affiliation: Division of Pediatric Hematology and Oncology, Children's Research Center, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität München, Lindwurmstrasse 2a, 80337, Munich, Germany. Irene.Schmid@med.uni-muenchen.de.
authors.forename: Irene
authors.initials: I
authors.lastname: Schmid
mesh_terms: D002453:Cell Cycle; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002465:Cell Movement; D018932:Chemokine CCL2 / Q000235:genetics; D019938:Cyclin D1 / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D007948:Leukemia, Monocytic, Acute / Q000235:genetics* / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics* / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism*
chemical_list: C111835:CCL2 protein, human; C530104:CCND1 protein, human; D018932:Chemokine CCL2; C578471:MIRN511 microRNA, human; C474558:MLL-AF9 fusion protein, human; D035683:MicroRNAs; D015514:Oncogene Proteins, Fusion; D019938:Cyclin D1; D051788:Myeloid-Lymphoid Leukemia Protein