Abstract
Abstract
Transcription factors are frequently altered in leukemia through chromosomal translocation, mutation or aberrant expression. AML1-ETO, a fusion protein generated by the t(8;21) translocation in acute myeloid leukemia (AML), is a transcription factor implicated in both gene repression and activation. AML1-ETO exists as dimer/oligomer through its NHR2 dimerization domain. Given that the AML1-ETO dimerization has been shown to be critical for its leukemogenic activity, it is important to identify coregulatory factors that “read” the NHR2 dimerization and contribute to leukemogenesis. We now show that, in leukemic cells, AML1-ETO resides in and functions through a stable protein complex (AETFC) that contains several hematopoietic transcription factors and cofactors. These AETFC components stabilize the complex through multivalent interactions, provide multiple DNA-binding domains for diverse target genes, colocalize genome-wide, cooperatively regulate gene expression, and contribute to leukemogenesis. Within the AETFC complex, the AML1-ETO dimerization is required for a specific interaction between the dimerized NHR2 domain and a novel NHR2-binding (N2B) motif in E proteins. Crystallographic study of the NHR2-N2B complex reveals a unique interaction pattern in which an N2B peptide makes direct contact with side chains of two NHR2 domains as a dimer, providing a novel model of how dimeric transcription factors create a new protein-binding interface through dimerization. Intriguingly, disruption of this interaction by point mutations abrogates AML1-ETO-induced hematopoietic stem cell self-renewal and leukemogenesis. These results reveal new mechanisms of action of AML1-ETO in leukemogenesis and provide potential therapeutic possibilities for targeting t(8;21)+ AML.
Citation Format: Xiao-Jian Sun, Zhanxin Wang, Lan Wang, Yanwen Jiang, T. David Soong, Nils Kost, Wei-Yi Chen, Olivier Elemento, Wolfgang Fischle, Ari Melnick, Dinshaw J. Patel, Stephen D. Nimer, Robert G. Roeder. A stable transcription factor complex nucleated by dimeric AML1-ETO controls leukemogenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-111. doi:10.1158/1538-7445.AM2013-LB-111