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CANCER STEM CELLS |
Departments of aPathology and
bDevelopmental Biology, Stanford University School Of Medicine, Stanford, California, USA;
cStanford Institute for Stem Cell Biology and Regenerative Medicine, Palo Alto, California, USA
Key Words. Bmi-1 • Green fluorescent protein • Hematopoietic stem cells • Leukemia
Correspondence: Naoki Hosen, M.D., Ph.D., Department of Cancer Stem Cell Biology, Osaka University, Graduate School of Medicine, 1-7, Yamada-Oka, Suita, Osaka 565-0871, Japan. Telephone: +81-6-6879-3676; Fax: +81-6-6879-3677; e-mail: hnaoki{at}imed3.med.osaka-u.ac.jp
Received April 17, 2006;
accepted for publication March 20, 2007.
Disclosure of potential conflicts of interest is found at the end of this article.
First published online in STEM CELLS EXPRESS March 29, 2007.
The ability to self-renew is essential for all kinds of stem cells regardless of tissue type. One of the best candidate genes involved in conferring self-renewal capacity is Bmi-1, which has been proven to be essential for the maintenance of both normal adult hematopoietic and leukemia stem cells, as well as adult neural stem cells. To investigate the possible role of Bmi-1 in other cell types that also self-renew, we generated Bmi-1-green fluorescent protein (GFP)-knock-in mice, in which GFP was expressed under the endogenous transcriptional regulatory elements of the Bmi-1 gene. Using these targeted reporter mice, we demonstrated that Bmi-1 is expressed in hematopoietic stem cells (HSCs) at its highest levels and downregulated upon commitment to differentiation. An in vivo reconstitution assay revealed that the frequency of HSCs was 1/16 in Bmi-1highc-kit+lin–Sca-1+ bone marrow (BM) cells and 1/49 in Bmi-1highlin– BM cells, suggesting that Bmi-1 may serve as a marker for normal HSCs. In murine leukemia models induced by P210BCR/ABL or TEL/PDGFßR + AML1/ETO, Bmi-1 was not overexpressed in leukemic HSCs, despite the increase in the HSC numbers. Bmi-1 was expressed at its highest levels in undifferentiated leukemia cells. Furthermore, in several other nonhematopoietic tissues, cells could be separated into distinct subpopulations with differential Bmi-1 expression. Thus, these mice allow for the isolation of viable Bmi-1-expressing cells and have the potential to become a useful tool for understanding the role of Bmi-1 in normal and cancer stem cells in multiple tissue types.
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