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  current news   Press   selected story    
     
  11 August 2014  
  Disruption of Runx1 and Runx3 leads to bone marrow failure and leukemia predisposition due to transcriptional and DNA repair defects
 
 




Authors
Chelsia Qiuxia Wang1,2,6, Vaidehi Krishnan1,6, Lavina Sierra Tay1,6, Desmond Wai Loon Chin1, Cai Ping Koh1, Jing Yuan Chooi1, Giselle Sek Suan Nah1,2, Linsen Du1, Bindya Jacob1, Namiko Yamashita1, Soak Kuan Lai1, Tuan Zea Tan1, Seiichi Mori1, Ichiro Tanuichi3, Vinay Tergaonkar2,5,  Yoshiaki Ito1,5, Motomi Osato1,2,4,5

1 - Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599,      Singapore
2 - Institute of Molecular and Cell Biology, A*STAR, Singapore 138673, Singapore
3 - Laboratory for Transcriptional Regulation, RIKEN Center for Integrative Medical Sciences, Yokohama,      Kanagawa 230-0045, Japan
4 - Institute of Bioengineering and Nanotechnology, A*STAR, Singapore 138669, Singapore
5 - Corresponding authors
6 - These authors contributed equally to this work.

Published online in Cell Reports on 24 July 2014.

Abstract
Cancer is caused by the accumulation of genetic defects. The RUNX family genes are among the most frequently inactivated genes in human leukemia and other cancers. Yet, it is currently unknown how RUNX-related cancers can be eliminated using targeted therapy. In the present study, a gene ablation experiment for Runx genes in mice yielded an unanticipated outcome. RUNX-deficient mice died due to two drastic hematopoietic diseases: bone marrow failure (BMF) and leukemia. The former refers to the inability to produce blood cells, whereas the latter means a massive expansion of abnormal hematopoietic cells. These apparently opposing clinical manifestations were reminiscent of a rare human congenital disease called Fanconi anemia (FA). DNA repair defects leads to either the eradication of unrepaired damaged cells or the rapid acquisition of cancer-causing genetic mutations in a single FA patient. The research team therefore intensively interrogated RUNX function in this DNA repair pathway. Indeed, they found that RUNX proteins have a critical and central role in the FA pathway by facilitating the recruitment of functionally active FA protein, monoubiquitinated FANCD2, to sites of DNA damage. This previously unappreciated link between RUNX and FA factors prompted the research team to test the possibility that a drug originally designed for killing a limited type of cancer cells with DNA repair defects could now be applied for pervasive leukemias and cancers harbouring RUNX alterations, which were earlier never thought to have DNA repair defects. In fact, the drug worked well, at least in cell culture experiments. Further drug efficacy testing is currently underway, employing mouse leukemia models, as a preclinical study.

Figure Legend: Schematic diagram illustrating the importance of RUNX proteins in recruitment of monoubiquitinated FANCD2/FANCI heterodimer to DNA damage foci to facilitate DNA repair after detection of ICLs at replication forks (top). In the absence of RUNX, FANCD2/I can still be monoubiquitinated, but recruitment to DNA damage foci is abrogated, leading to defective DNA damage repair. Such unrepaired DNA damage can lead to either apoptosis of the cells or accumulation of mutations and subsequent tumor formation.

For more information on Vinay TERGAONKAR's lab, please click here.