Submitted April 23, 2008
Accepted November 10, 2008
RUNX1/AML1 DNA binding domain and ETO/MTG8 NHR2 dimerization domain are critical to AML1-ETO9a leukemogenesis
Ming Yan, Eun-Young Ahn, Scott W. Hiebert, and Dong-Er Zhang*
Moores UCSD Cancer Center, University of California San Diego, La Jolla, CA, United States
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, 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.
The 8;21 translocation, which involves the gene encoding the RUNX family DNA binding transcription factor AML1 (RUNX1) on chromosome 21 and the ETO (MTG8) gene on chromosome 8, generates AML1-ETO fusion proteins. Previous analyses have demonstrated that full length AML1-ETO blocks AML1 function and requires additional mutagenic events to promote leukemia. More recently, we have identified an alternatively spliced form of AML1-ETO, AML1-ETO9a, from t(8;21) acute myeloid leukemia (AML) patient samples. AML1-ETO9a lacks the C-terminal NHR3 and NHR4 domains of AML1-ETO and is highly leukemogenic in the mouse model. Here, we report that the AML1 DNA binding domain and the ETO NHR2 dimerization domain, but not the ETO NHR1 domain are critical for the induction of acute myeloid leukemia by AML1-ETO9a. A region between NHR1 and NHR2 affects latency of leukemogenesis. These results provide valuable insight into further analysis of the molecular mechanism of t(8;21) in leukemogenesis.
