title: Oncomir miR-125b regulates hematopoiesis by targeting the gene Lin28A.
abstract: MicroRNA-125b (miR-125b) is up-regulated in patients with leukemia. Overexpression of miR-125b alone in mice causes a very aggressive, transplantable myeloid leukemia. Before leukemia, these mice do not display elevation of white blood cells in the spleen or bone marrow; rather, the hematopoietic compartment shows lineage-skewing, with myeloid cell numbers dramatically increased and B-cell numbers severely diminished. miR-125b exerts this effect by up-regulating the number of common myeloid progenitors while inhibiting development of pre-B cells. We applied a miR-125b sponge loss of function system in vivo to show that miR-125b physiologically regulates hematopoietic development. Investigating the mechanism by which miR-125b regulates hematopoiesis, we found that, among a panel of candidate targets, the mRNA for Lin28A, an induced pluripotent stem cell gene, was most repressed by miR-125b in mouse hematopoietic stem and progenitor cells. Overexpressing Lin28A in the mouse hematopoietic system mimicked the phenotype observed on inhibiting miR-125b function, leading to a decrease in hematopoietic output. Relevant to the miR-125b overexpression phenotype, we also found that knockdown of Lin28A led to hematopoietic lineage-skewing, with increased myeloid and decreased B-cell numbers. Thus, the miR-125b target Lin28A is an important regulator of hematopoiesis and a primary target of miR-125b in the hematopoietic system.
authors.affiliation: Departments of Biology and Computing and Mathematical Sciences, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Aadel A
authors.initials: AA
authors.lastname: Chaudhuri
authors.forename: Alex Yick-Lun
authors.initials: AY
authors.lastname: So
authors.forename: Arnav
authors.initials: A
authors.lastname: Mehta
authors.forename: Aarathi
authors.initials: A
authors.lastname: Minisandram
authors.forename: Nikita
authors.initials: N
authors.lastname: Sinha
authors.forename: Vanessa D
authors.initials: VD
authors.lastname: Jonsson
authors.forename: Dinesh S
authors.initials: DS
authors.lastname: Rao
authors.forename: Ryan M
authors.initials: RM
authors.lastname: O'Connell
authors.forename: David
authors.initials: D
authors.lastname: Baltimore
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D002452:Cell Count; D002454:Cell Differentiation / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic; D006410:Hematopoiesis / Q000235:genetics*; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology; D009361:Neoplasm Invasiveness; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C488352:Lin-28 protein, mouse; D035683:MicroRNAs; C527468:Mirn125 microRNA, mouse; D016601:RNA-Binding Proteins