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A role for GPx3 in activity of normal and leukemia stem cells

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Official URL:https://doi.org/10.1084/jem.20102386
PubMed:View item in PubMed
Creators Name:Herault, O. and Hope, K.J. and Deneault, E. and Mayotte, N. and Chagraoui, J. and Wilhelm, B.T. and Cellot, S. and Sauvageau, M. and Andrade-Navarro, M.A. and Hebert, J. and Sauvageau, G.
Journal Title:Journal of Experimental Medicine
Journal Abbreviation:J Exp Med
Volume:209
Number:5
Page Range:895-901
Date:7 May 2012
Keywords:Base Sequence, Cell Line, Confocal Microscopy, DNA-Binding Proteins, DNA Sequence Analysis, Flow Cytometry, Fluorescence, Gene Expression Profiling, Genetic Vectors, Glutathione Peroxidase, Homeodomain Proteins, Leukemia, Molecular Sequence Data, Neoplasm Proteins, Neoplastic Gene Expression Regulation, Neoplastic Stem Cells, Reactive Oxygen Species, Real-Time Polymerase Chain Reaction, Southern Blotting, Stem Cells, Transcription Factors, Animals, Mice
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.
ISSN:0022-1007
Publisher:Rockefeller University Press (U.S.A.)
Item Type:Article

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