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 Blood, 15 August 2008, Vol. 112, No. 4, pp. 1392-1401.
Prepublished online as a Blood First Edition Paper on May 29, 2008; DOI 10.1182/blood-2007-11-124735.

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Submitted November 26, 2007
Accepted May 7, 2008

t(8;21)(q22;q22) fusion proteins preferentially bind to duplicated AML1/RUNX1 DNA binding sequences to differentially regulate gene expression

Akiko Joo Okumura, Luke F. Peterson, Fumihiko Okumura, Anita Boyapati, and Dong-Er Zhang*

Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, United States
Department of Pathology and Division of Biological Sciences, University of California San Diego, La Jolla, CA, United States

* Corresponding author; email: d7zhang{at}ucsd.edu.

Chromosome abnormalities are frequently associated with cancer development. The 8;21(q22;q22) chromosomal translocation is one of the most common chromosome abnormalities identified in leukemia. It generates fusion proteins between AML1 and ETO. Since AML1 is a well defined DNA binding protein, AML1-ETO fusion proteins have been recognized as DNA binding proteins interacting with the same consensus DNA binding site as AML1. The alteration of AML1 target gene expression due to the presence of AML1-ETO is related to the development of leukemia. Here, using a 25 bp random double-stranded oligonucleotide library and a PCR based DNA binding site screen, we show that compared to native AML1, AML1-ETO fusion proteins preferentially bind to DNA sequences with duplicated AML1 consensus sites. This finding is further confirmed by both in vitro and in vivo DNA-protein interaction assays. These results suggest that AML1-ETO fusion proteins have a selective preference for certain AML1 target genes that contain multimerized AML1 consensus sites in their regulatory elements. Such selected regulation provides an important molecular mechanism for the dysregulation of gene expression during cancer development.


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M. Yan, E.-Y. Ahn, S. W. Hiebert, and D.-E. Zhang
RUNX1/AML1 DNA-binding domain and ETO/MTG8 NHR2-dimerization domain are critical to AML1-ETO9a leukemogenesis
Blood, January 22, 2009; 113(4): 883 - 886.
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