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First published online September 6, 2007
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2007-0061v1
25/12/2976    most recent
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Submitted on January 25, 2007
Accepted on August 28, 2007

CANCER STEM CELLS

Runx1 Protects Hematopoietic Stem/progenitor Cells from Oncogenic Insult

Lena Motoda 1, Motomi Osato 2, Namiko Yamashita 3, Bindya Jacob 3, Lynnette Q. Chen 3, Masatoshi Yanagida 3, Hiroshi Ida 3, Hee Jun Wee 3, Alfred X. Sun 3, Ichiro Taniuchi 4, Dan Littman 5, Yoshiaki Ito 2*

1 Institute of Molecular and Cell Biology, Singapore, Department of Pediatric Science, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
2 Institute of Molecular and Cell Biology, Singapore, Oncology Research Institute, National University of Singapore, Singapore
3 Institute of Molecular and Cell Biology, Singapore
4 RIKEN, Research Center for Allergy and Immunology, Yokohama, Japan
5 New York University, New York, U.S.A.

* To whom correspondence should be addressed. E-mail: itoy{at}imcb.a-star.edu.sg.


  Abstract

The RUNX1/AML1 gene encodes a transcription factor essential for the generation of hematopoietic stem cells and is frequently targeted in human leukemia. In humanRUNX1-related leukemias, the RAS pathway is often concurrently mutated, but the mechanism of the synergism remains elusive. Here, we found that inactivation of Runx1 in mouse bone marrow cells results in an increase in the stem/progenitor cell fraction due to suppression of apoptosis and elevated expression of the polycomb gene Bmi-1, which is important for stem cell self-renewal. Introduction of oncogenic N-RAS into wild-type cells, in contrast, reduced the stem/progenitor cell fraction due to senescence, apoptosis and differentiation. Such detrimental events occurred presumably due to the cellular fail-safe program, although hyperproliferation was induced initially by an oncogenic stimulus. Runx1 insufficiency appears to impair such fail-safe mechanism, particularly in the stem/progenitor cells, thereby supporting the clonal maintenance of leukemia-initiating cells expressing an activated oncogene.

Key Words. AML1, Runx, stem cell, senescence, apoptosis




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