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

25 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

Fingerprint

Hematopoietic Stem Cells
Stem cells
Maintenance
Cell Cycle
Cells
S 6
Cell Aging
Oncogene Proteins
Ubiquitin
Cell culture
Cell Differentiation
Protein Isoforms
Proteins
Modulation
Degradation
Substrates

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

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

Ex vivo maintenance of hematopoietic stem cells by quiescence induction through Fbxw7α overexpression. / Iriuchishima, Hirono; Takubo, Keiyo; Matsuoka, Sahoko; Onoyama, Ichiro; Nakayama, Keiichi I.; Nojima, Yoshihisa; Suda, Toshio.

In: Blood, Vol. 117, No. 8, 24.02.2011, p. 2373-2377.

Research output: Contribution to journalArticle

Iriuchishima, H, Takubo, K, Matsuoka, S, Onoyama, I, Nakayama, KI, Nojima, Y & Suda, T 2011, 'Ex vivo maintenance of hematopoietic stem cells by quiescence induction through Fbxw7α overexpression', Blood, vol. 117, no. 8, pp. 2373-2377. https://doi.org/10.1182/blood-2010-07-294801
Iriuchishima H, Takubo K, Matsuoka S, Onoyama I, Nakayama KI, Nojima Y et al. Ex vivo maintenance of hematopoietic stem cells by quiescence induction through Fbxw7α overexpression. Blood. 2011 Feb 24;117(8):2373-2377. https://doi.org/10.1182/blood-2010-07-294801
Iriuchishima, Hirono ; Takubo, Keiyo ; Matsuoka, Sahoko ; Onoyama, Ichiro ; Nakayama, Keiichi I. ; Nojima, Yoshihisa ; Suda, Toshio. / Ex vivo maintenance of hematopoietic stem cells by quiescence induction through Fbxw7α overexpression. In: Blood. 2011 ; Vol. 117, No. 8. pp. 2373-2377.
@article{d14df90c69fc4cc6b8ec9176fc7acf3f,
title = "Ex vivo maintenance of hematopoietic stem cells by quiescence induction through Fbxw7α overexpression",
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.",
author = "Hirono Iriuchishima and Keiyo Takubo and Sahoko Matsuoka and Ichiro Onoyama and Nakayama, {Keiichi I.} and Yoshihisa Nojima and Toshio Suda",
year = "2011",
month = "2",
day = "24",
doi = "10.1182/blood-2010-07-294801",
language = "English",
volume = "117",
pages = "2373--2377",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "8",

}

TY - JOUR

T1 - Ex vivo maintenance of hematopoietic stem cells by quiescence induction through Fbxw7α overexpression

AU - Iriuchishima, Hirono

AU - Takubo, Keiyo

AU - Matsuoka, Sahoko

AU - Onoyama, Ichiro

AU - Nakayama, Keiichi I.

AU - Nojima, Yoshihisa

AU - Suda, Toshio

PY - 2011/2/24

Y1 - 2011/2/24

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=79952176472&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79952176472&partnerID=8YFLogxK

U2 - 10.1182/blood-2010-07-294801

DO - 10.1182/blood-2010-07-294801

M3 - Article

C2 - 21190997

AN - SCOPUS:79952176472

VL - 117

SP - 2373

EP - 2377

JO - Blood

JF - Blood

SN - 0006-4971

IS - 8

ER -