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Science 27 August 2004:
Vol. 305. no. 5688, pp. 1286 - 1289
DOI: 10.1126/science.1097937
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Reports

E Protein Silencing by the Leukemogenic AML1-ETO Fusion Protein

Jinsong Zhang,1 Markus Kalkum,2 Soichiro Yamamura,1 Brian T. Chait,2 Robert G. Roeder1*

The AML1-ETO fusion protein, generated by the t(8;21) chromosomal translocation, is causally involved in nearly 15% of acute myeloid leukemia (AML) cases. This study shows that AML1-ETO, as well as ETO, inhibits transcriptional activation by E proteins through stable interactions that preclude recruitment of p300/CREB-binding protein (CBP) coactivators. These interactions are mediated by a conserved ETO TAF4 homology domain and a 17–amino acid p300/CBP and ETO target motif within AD1 activation domains of E proteins. In t(8;21) leukemic cells, very stable interactions between AML1-ETO and E proteins underlie a t(8;21) translocation-specific silencing of E protein function through an aberrant cofactor exchange mechanism. These studies identify E proteins as AML1-ETO targets whose dysregulation may be important for t(8;21) leukemogenesis, as well as an E protein silencing mechanism that is distinct from 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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