title: MicroRNA-223 dose levels fine tune proliferation and differentiation in human cord blood progenitors and acute myeloid leukemia.
abstract: A precise understanding of the role of miR-223 in human hematopoiesis and in the pathogenesis of acute myeloid leukemia (AML) is still lacking. By measuring miR-223 expression in blasts from 115 AML patients, we found significantly higher miR-223 levels in patients with favorable prognosis, whereas patients with low miR-223 expression levels were associated with worse outcome. Furthermore, miR-223 was hierarchically expressed in AML subpopulations, with lower expression in leukemic stem cell-containing fractions. Genetic depletion of miR-223 decreased the leukemia initiating cell (LIC) frequency in a myelomonocytic AML mouse model, but it was not mandatory for rapid-onset AML. To relate these observations to physiologic myeloid differentiation, we knocked down or ectopically expressed miR-223 in cord-blood CD34⁺ cells using lentiviral vectors. Although miR-223 knockdown delayed myeloerythroid precursor differentiation in vitro, it increased myeloid progenitors in vivo following serial xenotransplantation. Ectopic miR-223 expression increased erythropoiesis, T lymphopoiesis, and early B lymphopoiesis in vivo. These findings broaden the role of miR-223 as a regulator of the expansion/differentiation equilibrium in hematopoietic stem and progenitor cells where its impact is dose- and differentiation-stage-dependent. This also explains the complex yet minor role of miR-223 in AML, a heterogeneous disease with variable degree of myeloid differentiation.
authors.affiliation: San Raffaele Hospital, Telethon Institute for Gene Therapy and Vita-Salute University, Milan, Italy.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Gentner
authors.affiliation: Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Pochert
authors.affiliation: Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.
authors.forename: Arefeh
authors.initials: A
authors.lastname: Rouhi
authors.affiliation: San Raffaele Hospital, Telethon Institute for Gene Therapy and Vita-Salute University, Milan, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Boccalatte
authors.affiliation: San Raffaele Hospital, Telethon Institute for Gene Therapy and Vita-Salute University, Milan, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Plati
authors.affiliation: Department of Medicine II, Center for Internal Medicine at the Goethe-University, Frankfurt, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Berg
authors.affiliation: Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Su Ming
authors.initials: SM
authors.lastname: Sun
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Mah
authors.affiliation: Department of Chemistry and Biochemistry, Gene Center and Laboratory of Molecular Biology, Ludwig Maximilians University München, Munich, Germany.
authors.forename: Milijana
authors.initials: M
authors.lastname: Mirkovic-Hösle
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Jens
authors.initials: J
authors.lastname: Ruschmann
authors.affiliation: Institute of Experimental Cancer Research, Comprehensive Cancer Centre, University Hospital of Ulm, Ulm, Germany.
authors.forename: Andrew
authors.initials: A
authors.lastname: Muranyi
authors.affiliation: Institute for Pharmakology and Toxicology, Technical University, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Leierseder
authors.affiliation: Department of Medical Genetics, University of Calgary, Calgary, Canada.
authors.forename: Bob
authors.initials: B
authors.lastname: Argiropoulos
authors.affiliation: Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Starczynowski
authors.affiliation: Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Aly
authors.initials: A
authors.lastname: Karsan
authors.affiliation: Department of Hematology, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Heuser
authors.affiliation: Department of Medicine II, Center for Internal Medicine at the Goethe-University, Frankfurt, Germany.
authors.forename: Donna
authors.initials: D
authors.lastname: Hogge
authors.affiliation: The Stem Cell Program, Department of Medicine, Boston Children's Hospital, Boston, MA, USA.
authors.forename: Fernando D
authors.initials: FD
authors.lastname: Camargo
authors.affiliation: Institute for Pharmakology and Toxicology, Technical University, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Engelhardt
authors.affiliation: Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
authors.affiliation: Institute of Experimental Cancer Research, Comprehensive Cancer Centre, University Hospital of Ulm, Ulm, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Buske
authors.affiliation: Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Mojca
authors.initials: M
authors.lastname: Jongen-Lavrencic
authors.affiliation: San Raffaele Hospital, Telethon Institute for Gene Therapy and Vita-Salute University, Milan, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Naldini
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: R Keith
authors.initials: RK
authors.lastname: Humphries
authors.affiliation: Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany. Electronic address: florian.kuchenbauer@uni-ulm.de.
authors.forename: Florian
authors.initials: F
authors.lastname: Kuchenbauer
mesh_terms: D000328:Adult; D000818:Animals; D049109:Cell Proliferation / Q000235:genetics; D004920:Erythropoiesis / Q000235:genetics; D005260:Female; D005312:Fetal Blood / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D038041:Lymphopoiesis / Q000235:genetics; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D008875:Middle Aged; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D012334:RNA, Neoplasm / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D035683:MicroRNAs; D012334:RNA, Neoplasm; C525067:MIR223, human; C544877:MIRN223 microRNA, mouse