title: MicroRNA-126-mediated control of cell fate in B-cell myeloid progenitors as a potential alternative to transcriptional factors.
abstract: Lineage specification is thought to be largely regulated at the level of transcription, where lineage-specific transcription factors drive specific cell fates. MicroRNAs (miR), vital to many cell functions, act posttranscriptionally to decrease the expression of target mRNAs. MLL-AF4 acute lymphocytic leukemia exhibits both myeloid and B-cell surface markers, suggesting that the transformed cells are B-cell myeloid progenitor cells. Through gain- and loss-of-function experiments, we demonstrated that microRNA 126 (miR-126) drives B-cell myeloid biphenotypic leukemia differentiation toward B cells without changing expression of E2A immunoglobulin enhancer-binding factor E12/E47 (E2A), early B-cell factor 1 (EBF1), or paired box protein 5, which are critical transcription factors in B-lymphopoiesis. Similar induction of B-cell differentiation by miR-126 was observed in normal hematopoietic cells in vitro and in vivo in uncommitted murine c-Kit(+)Sca1(+)Lineage(-) cells, with insulin regulatory subunit-1 acting as a target of miR-126. Importantly, in EBF1-deficient hematopoietic progenitor cells, which fail to differentiate into B cells, miR-126 significantly up-regulated B220, and induced the expression of B-cell genes, including recombination activating genes-1/2 and CD79a/b. These data suggest that miR-126 can at least partly rescue B-cell development independently of EBF1. These experiments show that miR-126 regulates myeloid vs. B-cell fate through an alternative machinery, establishing the critical role of miRNAs in the lineage specification of multipotent mammalian cells.
authors.affiliation: Division of Hematological Malignancy, Regenerative Medical Science, Tokai University School of Medicine, Kanagawa 259-1193, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Okuyama
authors.forename: Tomokatsu
authors.initials: T
authors.lastname: Ikawa
authors.forename: Bernhard
authors.initials: B
authors.lastname: Gentner
authors.forename: Katsuto
authors.initials: K
authors.lastname: Hozumi
authors.forename: Ratanakanit
authors.initials: R
authors.lastname: Harnprasopwat
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.forename: Riu
authors.initials: R
authors.lastname: Yamashita
authors.forename: Daon
authors.initials: D
authors.lastname: Ha
authors.forename: Takae
authors.initials: T
authors.lastname: Toyoshima
authors.forename: Bidisha
authors.initials: B
authors.lastname: Chanda
authors.forename: Toyotaka
authors.initials: T
authors.lastname: Kawamata
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Yokoyama
authors.forename: Shusheng
authors.initials: S
authors.lastname: Wang
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Ando
authors.forename: Harvey F
authors.initials: HF
authors.lastname: Lodish
authors.forename: Arinobu
authors.initials: A
authors.lastname: Tojo
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawamoto
authors.forename: Ai
authors.initials: A
authors.lastname: Kotani
mesh_terms: D000704:Analysis of Variance; D001402:B-Lymphocytes / Q000378:metabolism; D015153:Blotting, Western; D016026:Bone Marrow Transplantation; D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000235:genetics* / Q000276:immunology; D017931:DNA Primers; D020869:Gene Expression Profiling; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D015448:Leukemia, B-Cell / Q000378:metabolism*; D008156:Luciferases; D035683:MicroRNAs / Q000378:metabolism*; D023461:Myeloid Progenitor Cells; D009841:Oligonucleotides / Q000235:genetics; D018709:Statistics, Nonparametric; D015534:Trans-Activators / Q000378:metabolism; D058127:Transcription Factor 3 / Q000378:metabolism
chemical_list: D017931:DNA Primers; C081976:EBF1 protein, human; C545201:MIRN126 microRNA, mouse; D035683:MicroRNAs; D009841:Oligonucleotides; D015534:Trans-Activators; D058127:Transcription Factor 3; D008156:Luciferases
keywords: cell fate decision; lymphopoiesis
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