title: miR-9 is a tumor suppressor in pediatric AML with t(8;21).
abstract: MicroRNAs (miRNAs) play a pivotal role in the regulation of hematopoiesis and development of leukemia. Great interest emerged in modulating miRNA expression for therapeutic purposes. In order to identify miRNAs, which specifically suppress leukemic growth of acute myeloid leukemia (AML) with t(8;21), inv(16) or mixed lineage leukemia (MLL) rearrangement by inducing differentiation, we conducted a miRNA expression profiling in a cohort of 90 cytogenetically characterized, de novo pediatric AML cases. Four miRNAs, specifically downregulated in MLL-rearranged, t(8;21) or inv(16) AMLs, were characterized by their tumor-suppressive properties in cell lines representing those respective cytogenetic groups. Among those, forced expression of miR-9 reduced leukemic growth and induced monocytic differentiation of t(8;21) AML cell lines in vitro and in vivo. The tumor-suppressive functions of miR-9 were specifically restricted to AML cell lines and primary leukemic blasts with t(8;21). On the other hand, these functions were not evident in AML blasts from patients with MLL rearrangements. We showed that miR-9 exerts its effects through the cooperation with let-7 to repress the oncogenic LIN28B/HMGA2 axis. Thus, miR-9 is a tumor suppressor-miR which acts in a stringent cell context-dependent manner.
authors.affiliation: Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Emmrich
authors.affiliation: Pediatric Oncology/Hematology/Biochemistry, Erasmus MC/Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: J E
authors.initials: JE
authors.lastname: Katsman-Kuipers
authors.affiliation: Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Henke
authors.affiliation: Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: M E
authors.initials: ME
authors.lastname: Khatib
authors.affiliation: Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Jammal
authors.affiliation: Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Engeland
authors.affiliation: Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Dasci
authors.affiliation: Pediatric Oncology/Hematology/Biochemistry, Erasmus MC/Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: C M
authors.initials: CM
authors.lastname: Zwaan
authors.affiliation: Pediatric Oncology/Hematology/Biochemistry, Erasmus MC/Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: M L
authors.initials: ML
authors.lastname: den Boer
authors.affiliation: Pediatric Oncology/Hematology/Biochemistry, Erasmus MC/Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: L
authors.initials: L
authors.lastname: Verboon
authors.affiliation: Pediatric Hematology/Oncology, Charles University and University Hospital Motol, Prague, Czech Republic.
authors.forename: J
authors.initials: J
authors.lastname: Stary
authors.affiliation: Hematology, St. Louis Hospital, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Baruchel
authors.affiliation: Dutch Childhood Oncology Group (DCOG), The Hague, The Netherlands.
authors.forename: V
authors.initials: V
authors.lastname: de Haas
authors.affiliation: Pediatric Oncology/Hematology/Biochemistry, Erasmus MC/Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: A A
authors.initials: AA
authors.lastname: Danen-van Oorschot
authors.affiliation: Pediatric Oncology/Hematology/Biochemistry, Erasmus MC/Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Fornerod
authors.affiliation: Pediatric Oncology/Hematology/Biochemistry, Erasmus MC/Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Pieters
authors.affiliation: Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Reinhardt
authors.affiliation: Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: J H
authors.identifier: 0000000210700727
authors.initials: JH
authors.lastname: Klusmann
authors.affiliation: Pediatric Oncology/Hematology/Biochemistry, Erasmus MC/Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: M M
authors.initials: MM
authors.lastname: van den Heuvel-Eibrink
mesh_terms: D000818:Animals; D002455:Cell Division; D002648:Child; D002891:Chromosomes, Human, Pair 21; D002898:Chromosomes, Human, Pair 8; D005260:Female; D005434:Flow Cytometry; D016147:Genes, Tumor Suppressor; D064593:Heterografts; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D014178:Translocation, Genetic
chemical_list: C541874:MIRN92 microRNA, human; D035683:MicroRNAs