The Journal of Experimental Medicine
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Published online 5 September 2006 doi:10.1084/jem.20052477
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 10, 2247-2253
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BRIEF DEFINITIVE REPORT

 Differential impact of Ink4a and Arf on hematopoietic stem cells and their bone marrow microenvironment in Bmi1-deficient mice

Hideyuki Oguro1,2, Atsushi Iwama2, Yohei Morita1, Takehiko Kamijo3, Maarten van Lohuizen4, and Hiromitsu Nakauchi1

1 Laboratory of Stem Cell Therapy, Center for Experimental Medicine, Institute of Medical Sciences, University of Tokyo, Tokyo 108-8679, Japan
2 Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
3 Division of Biochemistry, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan
4 Division of Molecular Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands

CORRESPONDENCE Atsushi Iwama: aiwama{at}faculty.chiba-u.jp OR Hiromitsu Nakauchi: nakauchi{at}ims.u-tokyo.ac.jp

The polycomb group (PcG) protein Bmi1 plays an essential role in the self-renewal of hematopoietic and neural stem cells. Derepression of the Ink4a/Arf gene locus has been largely attributed to Bmi1-deficient phenotypes in the nervous system. However, its role in hematopoietic stem cell (HSC) self-renewal remained undetermined. In this study, we show that derepressed p16Ink4a and p19Arf in Bmi1-deficient mice were tightly associated with a loss of self-renewing HSCs. The deletion of both Ink4a and Arf genes substantially restored the self-renewal capacity of Bmi1–/– HSCs. Thus, Bmi1 regulates HSCs by acting as a critical failsafe against the p16Ink4a- and p19Arf-dependent premature loss of HSCs. We further identified a novel role for Bmi1 in the organization of a functional bone marrow (BM) microenvironment. The BM microenvironment in Bmi1–/– mice appeared severely defective in supporting hematopoiesis. The deletion of both Ink4a and Arf genes did not considerably restore the impaired BM microenvironment, leading to a sustained postnatal HSC depletion in Bmi1–/–Ink4a-Arf–/– mice. Our findings unveil a differential role of derepressed Ink4a and Arf on HSCs and their BM microenvironment in Bmi1-deficient mice. Collectively, Bmi1 regulates self-renewing HSCs in both cell-autonomous and nonautonomous manners.


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