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

Hirono Iriuchishima, Keiyo Takubo, Sahoko Matsuoka, Ichiro Onoyama, Keiichi I. Nakayama, Yoshihisa Nojima, Toshio Suda

Research output: Contribution to journalArticle

28 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2373-2377
Number of pages5
JournalBlood
Volume117
Issue number8
DOIs
Publication statusPublished - 2011 Feb 24

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Iriuchishima, H., Takubo, K., Matsuoka, S., Onoyama, I., Nakayama, K. I., Nojima, Y., & Suda, T. (2011). Ex vivo maintenance of hematopoietic stem cells by quiescence induction through Fbxw7α overexpression. Blood, 117(8), 2373-2377. https://doi.org/10.1182/blood-2010-07-294801