title: A role for GPx3 in activity of normal and leukemia stem cells.
abstract: The determinants of normal and leukemic stem cell self-renewal remain poorly characterized. We report that expression of the reactive oxygen species (ROS) scavenger glutathione peroxidase 3 (GPx3) positively correlates with the frequency of leukemia stem cells (LSCs) in Hoxa9+Meis1-induced leukemias. Compared with a leukemia with a low frequency of LSCs, a leukemia with a high frequency of LSCs showed hypomethylation of the Gpx3 promoter region, and expressed high levels of Gpx3 and low levels of ROS. LSCs and normal hematopoietic stem cells (HSCs) engineered to express Gpx3 short hairpin RNA (shRNA) were much less competitive in vivo than control cells. However, progenitor cell proliferation and differentiation was not affected by Gpx3 shRNA. Consistent with this, HSCs overexpressing Gpx3 were significantly more competitive than control cells in long-term repopulation experiments, and overexpression of the self-renewal genes Prdm16 or Hoxb4 boosted Gpx3 expression. In human primary acute myeloid leukemia samples, GPX3 expression level directly correlated with adverse prognostic outcome, revealing a potential novel target for the eradication of LSCs.
authors.affiliation: Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Olivier
authors.initials: O
authors.lastname: Herault
authors.forename: Kristin J
authors.initials: KJ
authors.lastname: Hope
authors.forename: Eric
authors.initials: E
authors.lastname: Deneault
authors.forename: Nadine
authors.initials: N
authors.lastname: Mayotte
authors.forename: Jalila
authors.initials: J
authors.lastname: Chagraoui
authors.forename: Brian T
authors.initials: BT
authors.lastname: Wilhelm
authors.forename: Sonia
authors.initials: S
authors.lastname: Cellot
authors.forename: Martin
authors.initials: M
authors.lastname: Sauvageau
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Andrade-Navarro
authors.forename: Josée
authors.initials: J
authors.lastname: Hébert
authors.forename: Guy
authors.initials: G
authors.lastname: Sauvageau
mesh_terms: D000818:Animals; D001483:Base Sequence; D015139:Blotting, Southern; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D005434:Flow Cytometry; D005453:Fluorescence; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D005822:Genetic Vectors / Q000235:genetics; D005979:Glutathione Peroxidase / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000378:metabolism*; D051379:Mice; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D013234:Stem Cells / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C090460:HOXB4 protein, human; D018398:Homeodomain Proteins; C000616391:MEIS1 protein, human; C000616392:Meis1 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; C416371:PRDM16 protein, human; D017382:Reactive Oxygen Species; D014157:Transcription Factors; C097899:homeobox protein HOXA9; C486484:GPX3 protein, human; D005979:Glutathione Peroxidase