Evi1 is essential for hematopoietic stem cell self-renewal, and its expression marks hematopoietic cells with long-term multilineage repopulating activity

Keisuke Kataoka, Tomohiko Sato, Akihide Yoshimi, Susumu Goyama, Takako Tsuruta, Hiroshi Kobayashi, Munetake Shimabe, Shunya Arai, Masahiro Nakagawa, Yoichi Imai, Keiki Kumano, Katsuyoshi Kumagai, Naoto Kubota, Takashi Kadowaki, Mineo Kurokawa

Research output: Contribution to journalArticlepeer-review

97 Citations (Scopus)

Abstract

Ecotropic viral integration site 1 (Evi1), a transcription factor of the SET/PR domain protein family, is essential for the maintenance of hematopoietic stem cells (HSCs) in mice and is overexpressed in several myeloid malignancies. Here, we generate reporter mice in which an internal ribosome entry site (IRES)-GFP cassette is knocked-in to the Evi1 locus. Using these mice, we find that Evi1 is predominantly expressed in long-term HSCs (LT-HSCs) in adult bone marrow, and in the hematopoietic stem/progenitor fraction in the aortagonad- mesonephros, placenta, and fetal liver of embryos. In both fetal and adult hematopoietic systems, Evi1 expression marks cells with long-term multilineage repopulating activity. When combined with conventional HSC surface markers, sorting according to Evi1 expression markedly enhances purification of cells with HSC activity. Evi1 heterozygosity leads to marked impairment of the self-renewal capacity of LT-HSCs, whereas overexpression of Evi1 suppresses differentiation and boosts self-renewal activity. Reintroduction of Evi1, but not Mds1-Evi1, rescues the HSC defects caused by Evi1 heterozygosity. Thus, in addition to documenting a specific relationship between Evi1 expression and HSC selfrenewal activity, these findings highlight the utility of Evi1-IRES-GFP reporter mice for the identification and sorting of functional HSCs.

Original languageEnglish
Pages (from-to)2403-2416
Number of pages14
JournalJournal of Experimental Medicine
Volume208
Issue number12
DOIs
Publication statusPublished - 2011 Nov 21
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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