title: Coordinate loss of a microRNA and protein-coding gene cooperate in the pathogenesis of 5q- syndrome.
abstract: Large chromosomal deletions are among the most common molecular abnormalities in cancer, yet the identification of relevant genes has proven difficult. The 5q- syndrome, a subtype of myelodysplastic syndrome (MDS), is a chromosomal deletion syndrome characterized by anemia and thrombocytosis. Although we have previously shown that hemizygous loss of RPS14 recapitulates the failed erythroid differentiation seen in 5q- syndrome, it does not affect thrombocytosis. Here we show that a microRNA located in the common deletion region of 5q- syndrome, miR-145, affects megakaryocyte and erythroid differentiation. We find that miR-145 functions through repression of Fli-1, a megakaryocyte and erythroid regulatory transcription factor. Patients with del(5q) MDS have decreased expression of miR-145 and increased expression of Fli-1. Overexpression of miR-145 or inhibition of Fli-1 decreases the production of megakaryocytic cells relative to erythroid cells, whereas inhibition of miR-145 or overexpression of Fli-1 has a reciprocal effect. Moreover, combined loss of miR-145 and RPS14 cooperates to alter erythroid-megakaryocytic differentiation in a manner similar to the 5q- syndrome. Taken together, these findings demonstrate that coordinate deletion of a miRNA and a protein-coding gene contributes to the phenotype of a human malignancy, the 5q- syndrome.
authors.affiliation: Department of Biology, Howard Hughes Medical Institute, USA.
authors.forename: Madhu S
authors.initials: MS
authors.lastname: Kumar
authors.forename: Anupama
authors.initials: A
authors.lastname: Narla
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nonami
authors.forename: Ann
authors.initials: A
authors.lastname: Mullally
authors.forename: Nadya
authors.initials: N
authors.lastname: Dimitrova
authors.forename: Brian
authors.initials: B
authors.lastname: Ball
authors.forename: J Randall
authors.initials: JR
authors.lastname: McAuley
authors.forename: Luke
authors.initials: L
authors.lastname: Poveromo
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Kutok
authors.forename: Naomi
authors.initials: N
authors.lastname: Galili
authors.forename: Azra
authors.initials: A
authors.lastname: Raza
authors.forename: Eyal
authors.initials: E
authors.lastname: Attar
authors.forename: D Gary
authors.initials: DG
authors.lastname: Gilliland
authors.forename: Tyler
authors.initials: T
authors.lastname: Jacks
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Ebert
mesh_terms: D000748:Anemia, Macrocytic / Q000209:etiology / Q000235:genetics*; D000818:Animals; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000235:genetics; D002872:Chromosome Deletion; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D041905:Erythroid Cells / Q000378:metabolism; D004920:Erythropoiesis / Q000235:genetics / Q000502:physiology; D006801:Humans; D019656:Loss of Heterozygosity; D008533:Megakaryocytes / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000473:pathology; D016366:Open Reading Frames / Q000235:genetics*; D051789:Proto-Oncogene Protein c-fli-1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D012269:Ribosomal Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: C541010:MIRN145 microRNA, human; D035683:MicroRNAs; D051789:Proto-Oncogene Protein c-fli-1; C526722:RPS14 protein, human; D012269:Ribosomal Proteins