Blood Journal
Leading the way in experimental and clinical research in hematology

Brief report
Ex vivo maintenance of hematopoietic stem cells by quiescence induction through Fbxw7α overexpression

  1. Hirono Iriuchishima1,2,*,
  2. Keiyo Takubo1,*,
  3. Sahoko Matsuoka1,
  4. Ichiro Onoyama3,
  5. Keiichi I. Nakayama3,
  6. Yoshihisa Nojima2, and
  7. Toshio Suda1
  1. 1Department of Cell Differentiation, Sakaguchi Laboratory of Developmental Biology, Keio University School of Medicine, Tokyo, Japan;
  2. 2Department of Medicine and Clinical Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan; and
  3. 3Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Higashi-ku, Fukuoka, Japan

Abstract

Cell-cycle quiescence in hematopoietic stem cells (HSCs) is essential for maintaining stemness by protecting cells from differentiation or senescence. F-box and WD-40 domain protein 7 (Fbxw7) maintains HSCs and suppresses leukemogenesis by mediating ubiquitin-dependent degradation of cell-cycle activators and oncoproteins. Fbxw7α was shown to be the preferentially expressed Fbxw7 isoform in primitive HSCs. Forced Fbxw7α expression in lineage marker Sca-1+c-Kit+ cells led to cell-cycle dormancy by reducing the protein levels of the Fbxw7 substrates c-Myc, Notch1, and phosphorylated S6 (a key downstream element of mTOR). Hypoxia, an essential factor for HSC quiescence, suppressed c-Myc in an Fbxw7α-dependent manner. Fbxw7α-overexpressing lineage marker Sca-1+c-Kit+ cells sustained high reconstitution capacities during in vitro culture. These data suggest that Fbxw7α sustains HSC dormancy through c-Myc, Notch1, and the mTOR pathways. The modulation of Fbxw7α expression or activity represents a promising new tool for ex vivo HSC maintenance.

  • Submitted July 6, 2010.
  • Accepted December 7, 2010.
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