title: MiR144/451 Expression Is Repressed by RUNX1 During Megakaryopoiesis and Disturbed by RUNX1/ETO.
abstract: A network of lineage-specific transcription factors and microRNAs tightly regulates differentiation of hematopoietic stem cells along the distinct lineages. Deregulation of this regulatory network contributes to impaired lineage fidelity and leukemogenesis. We found that the hematopoietic master regulator RUNX1 controls the expression of certain microRNAs, of importance during erythroid/megakaryocytic differentiation. In particular, we show that the erythorid miR144/451 cluster is epigenetically repressed by RUNX1 during megakaryopoiesis. Furthermore, the leukemogenic RUNX1/ETO fusion protein transcriptionally represses the miR144/451 pre-microRNA. Thus RUNX1/ETO contributes to increased expression of miR451 target genes and interferes with normal gene expression during differentiation. Furthermore, we observed that inhibition of RUNX1/ETO in Kasumi1 cells and in RUNX1/ETO positive primary acute myeloid leukemia patient samples leads to up-regulation of miR144/451. RUNX1 thus emerges as a key regulator of a microRNA network, driving differentiation at the megakaryocytic/erythroid branching point. The network is disturbed by the leukemogenic RUNX1/ETO fusion product.
authors.affiliation: Georg-Speyer-Haus, Institute for Tumorbiology and Experimental Therapy, Frankfurt, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Kohrs
authors.affiliation: Georg-Speyer-Haus, Institute for Tumorbiology and Experimental Therapy, Frankfurt, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Kolodziej
authors.affiliation: Georg-Speyer-Haus, Institute for Tumorbiology and Experimental Therapy, Frankfurt, Germany.
authors.forename: Olga N
authors.initials: ON
authors.lastname: Kuvardina
authors.affiliation: Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Herglotz
authors.affiliation: Georg-Speyer-Haus, Institute for Tumorbiology and Experimental Therapy, Frankfurt, Germany.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Yillah
authors.affiliation: Georg-Speyer-Haus, Institute for Tumorbiology and Experimental Therapy, Frankfurt, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Herkt
authors.affiliation: Georg-Speyer-Haus, Institute for Tumorbiology and Experimental Therapy, Frankfurt, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Piechatzek
authors.affiliation: Medical-University Goettingen, Transcriptome Analysis Laboratory, Goettingen, Germany.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Salinas Riester
authors.affiliation: Medical-University Goettingen, Transcriptome Analysis Laboratory, Goettingen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lingner
authors.affiliation: Department of Transfusion Medicine, Cell Therapeutics and Hemostaseology, Ludwig-Maximilian University Hospital, Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Wichmann
authors.affiliation: Institute for Transfusion Medicine and Immunohematology, Johann-Wolfgang-Goethe University and German Red Cross Blood Service, Frankfurt am Main, Germany.
authors.forename: Halvard
authors.initials: H
authors.lastname: Bonig
authors.affiliation: Institute for Transfusion Medicine and Immunohematology, Johann-Wolfgang-Goethe University and German Red Cross Blood Service, Frankfurt am Main, Germany.
authors.forename: Erhard
authors.initials: E
authors.lastname: Seifried
authors.affiliation: Department of Hematology, Medical Clinic and Polyclinic I, University Hospital Carl Gustav Carus, Dresden, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Platzbecker
authors.affiliation: Georg-Speyer-Haus, Institute for Tumorbiology and Experimental Therapy, Frankfurt, Germany.
authors.forename: Hind
authors.initials: H
authors.lastname: Medyouf
authors.affiliation: Georg-Speyer-Haus, Institute for Tumorbiology and Experimental Therapy, Frankfurt, Germany.
authors.forename: Manuel
authors.initials: M
authors.lastname: Grez
authors.affiliation: Georg-Speyer-Haus, Institute for Tumorbiology and Experimental Therapy, Frankfurt, Germany.|Institute for Transfusion Medicine and Immunohematology, Johann-Wolfgang-Goethe University and German Red Cross Blood Service, Frankfurt am Main, Germany.
authors.forename: Jörn
authors.initials: J
authors.lastname: Lausen
mesh_terms: D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage; D050676:Core Binding Factor Alpha 2 Subunit / Q000096:biosynthesis / Q000235:genetics*; D015973:Gene Expression Regulation, Leukemic; D053263:Gene Regulatory Networks / Q000235:genetics; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D008533:Megakaryocytes / Q000166:cytology; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; C531201:MIRN451 microRNA, human; D035683:MicroRNAs; D015514:Oncogene Proteins, Fusion; C493728:RUNX1 protein, human