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E Protein Silencing by the Leukemogenic AML1-ETO Fusion Protein
Jinsong Zhang,1Markus Kalkum,2Soichiro Yamamura,1Brian T. Chait,2Robert G. Roeder1*
The AML1-ETO fusion protein, generated by the t(8;21) chromosomaltranslocation, is causally involved in nearly 15% of acute myeloidleukemia (AML) cases. This study shows that AML1-ETO, as wellas ETO, inhibits transcriptional activation by E proteins throughstable interactions that preclude recruitment of p300/CREB-bindingprotein (CBP) coactivators. These interactions are mediatedby a conserved ETO TAF4 homology domain and a 17–aminoacid p300/CBP and ETO target motif within AD1 activation domainsof E proteins. In t(8;21) leukemic cells, very stable interactionsbetween AML1-ETO and E proteins underlie a t(8;21) translocation-specificsilencing of E protein function through an aberrant cofactorexchange mechanism. These studies identify E proteins as AML1-ETOtargets whose dysregulation may be important for t(8;21) leukemogenesis,as well as an E protein silencing mechanism that is distinctfrom that associated with differentiation-inhibitory proteins.
1 Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA. 2 Laboratory of Mass Spectrometry and Gaseous Ion Chemistry, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
* To whom correspondence should be addressed. E-mail: roeder{at}mail.rockefeller.edu
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