title: Dual mechanisms by which miR-125b represses IRF4 to induce myeloid and B-cell leukemias.
abstract: The oncomir microRNA-125b (miR-125b) is upregulated in a variety of human neoplastic blood disorders and constitutive upregulation of miR-125b in mice can promote myeloid and B-cell leukemia. We found that miR-125b promotes myeloid and B-cell neoplasm by inducing tumorigenesis in hematopoietic progenitor cells. Our study demonstrates that miR-125b induces myeloid leukemia by enhancing myeloid progenitor output from stem cells as well as inducing immortality, self-renewal, and tumorigenesis in myeloid progenitors. Through functional and genetic analyses, we demonstrated that miR-125b induces myeloid and B-cell leukemia by inhibiting interferon regulatory factor 4 (IRF4) but through distinct mechanisms; it induces myeloid leukemia through repressing IRF4 at the messenger RNA (mRNA) level without altering the genomic DNA and induces B-cell leukemia via genetic deletion of the gene encoding IRF4.
authors.affiliation: Department of Biology, California Institute of Technology, Pasadena, CA;
authors.forename: Alex Yick-Lun
authors.initials: AY
authors.lastname: So
authors.affiliation: Department of Biology, California Institute of Technology, Pasadena, CA;
authors.forename: Reeshelle
authors.initials: R
authors.lastname: Sookram
authors.affiliation: Department of Biology, California Institute of Technology, Pasadena, CA; Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA;
authors.forename: Aadel A
authors.initials: AA
authors.lastname: Chaudhuri
authors.affiliation: Department of Biology, California Institute of Technology, Pasadena, CA;
authors.forename: Aarathi
authors.initials: A
authors.lastname: Minisandram
authors.affiliation: Department of Biology, California Institute of Technology, Pasadena, CA;
authors.forename: David
authors.initials: D
authors.lastname: Cheng
authors.affiliation: Department of Biology, California Institute of Technology, Pasadena, CA;
authors.forename: Catherine
authors.initials: C
authors.lastname: Xie
authors.affiliation: Department of Biology, California Institute of Technology, Pasadena, CA;
authors.forename: Ee Lyn
authors.initials: EL
authors.lastname: Lim
authors.affiliation: Department of Biology, California Institute of Technology, Pasadena, CA;
authors.forename: Yvette Garcia
authors.initials: YG
authors.lastname: Flores
authors.affiliation: Department of Biology, California Institute of Technology, Pasadena, CA;
authors.forename: Shuai
authors.initials: S
authors.lastname: Jiang
authors.affiliation: Department of Biology, California Institute of Technology, Pasadena, CA;
authors.forename: Jocelyn Tammy
authors.initials: JT
authors.lastname: Kim
authors.affiliation: Department of Cognitive Science, University of California San Diego, La Jolla, CA; and.
authors.forename: Christopher
authors.initials: C
authors.lastname: Keown
authors.affiliation: Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH.
authors.forename: Parameswaran
authors.initials: P
authors.lastname: Ramakrishnan
authors.affiliation: Department of Biology, California Institute of Technology, Pasadena, CA;
authors.forename: David
authors.initials: D
authors.lastname: Baltimore
mesh_terms: D000818:Animals; D005260:Female; D017353:Gene Deletion; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D050835:Interferon Regulatory Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D015448:Leukemia, B-Cell / Q000209:etiology / Q000235:genetics* / Q000378:metabolism*; D007951:Leukemia, Myeloid / Q000209:etiology / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D000099218:Interferon Regulatory Factor-4
chemical_list: D050835:Interferon Regulatory Factors; D035683:MicroRNAs; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D000099218:Interferon Regulatory Factor-4; C531888:MIRN125 microRNA, human; C527468:Mirn125 microRNA, mouse