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  current news   Press   selected story    
     
  27th June  
 

Runx1 Protects Hematopoietic Stem/Progenitor Cells from Oncogenic Insult

 
 




Congratulations to Dr. Lena Motoda who was awarded the 3rd Annual STEM CELLS Young Investigator Award on June 20th, 2008 during the 6th International Stem Cell Symposium in Seoul, Korea. Each year, co-sponsored by the Symposium, STEM CELLS presents this $10,000 prize to a young scientist that has published the most important research findings in STEM CELLS as selected by a worldwide panel. Dr. Motoda received this prize for her research on the protective functions of RUNX1, conducted under the mentorship of Associate Professor Motomi Osato and Professor Yoshiaki Ito at the IMCB. Her work is a shining example of how understanding basic molecular mechanisms can help to unravel and prevent diseases and aid in the advancement of novel therapeutic strategies.

Authors
Motoda L, Osato M, Yamashita N, Jacob B, Chen LQ, Yanagida M, Ida H, Wee HJ, Sun AX, Taniuchi I, Littman D, Ito Y.

Published in Stem Cells 25:2976-86, 2007.

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 human RUNX1-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 because of senescence, apoptosis, and differentiation. Such detrimental events presumably occurred because of the cellular fail-safe program, although hyperproliferation was initially induced by an oncogenic stimulus. Runx1 insufficiency appears to impair such a fail-safe mechanism, particularly in the stem/progenitor cells, thereby supporting the maintenance of leukemia-initiating clone expressing an activated oncogene.

 
 


 
 

Figure Legend: Runx1 contributes to abortion of a leukemia-initiating clone. 
Runx1 contributes to abortion of a leukemia-initiating clone. The cellular fail-safe mechanism is active in Runx1+/+ stem/progenitor cells to eradicate cells carrying an oncogenic mutation. On the other hand, this mechanism is not fully functional in Runx1 insufficient status due to the up-regulation of Bmi-1and Bcl-2. A leukemia-initiating clone is therefore easily maintained, sequentially accumulating genetic changes, and eventually leads to the formation of a fully malignant clone.

Correspondence to Prof. Ito itoy@imcb.a-star.edu.sg

For more information on Prof. Ito’s lab, Please Click here.