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Journal Article

A stable transcription factor complex nucleated by oligomeric AML1-ETO controls leukaemogenesis.

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Kost,  N.
Research Group of Chromatin Biochemistry, MPI for Biophysical Chemistry, Max Planck Society;

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Fischle,  W.
Research Group of Chromatin Biochemistry, MPI for Biophysical Chemistry, Max Planck Society;

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Citation

Sun, X. J., Wang, Z. X., Jiang, Y., Kost, N., Soong, T. D., Chen, W. Y., et al. (2013). A stable transcription factor complex nucleated by oligomeric AML1-ETO controls leukaemogenesis. Nature, 500(7460), 93-97. doi: 10.1038/nature12287.


Cite as: https://hdl.handle.net/11858/00-001M-0000-0014-4CBF-5
Abstract
Transcription factors are frequently altered in leukaemia through chromosomal translocation, mutation or aberrant expression(1). AML1-ETO, a fusion protein generated by the t(8;21) translocation in acute myeloid leukaemia, is a transcription factor implicated in both gene repression and activation(2). AML1-ETO oligomerization, mediated by the NHR2 domain, is critical for leukaemogenesis(3-6), making it important to identify co-regulatory factors that 'read' the NHR2 oligomerization and contribute to leukaemogenesis(4). Here we show that, in human leukaemic cells, AML1-ETO resides in and functions through a stable AML1-ETO-containing transcription factor complex (AETFC) that contains several haematopoietic transcription (co)factors. These AETFC components stabilize the complex through multivalent interactions, provide multiple DNA-binding domains for diverse target genes, co-localize genome wide, cooperatively regulate gene expression, and contribute to leukaemogenesis. Within the AETFC complex, AML1-ETO oligomerization is required for a specific interaction between the oligomerized NHR2 domain and a novel NHR2-binding (N2B) motif in E proteins. Crystallographic analysis 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/oligomeric transcription factors create a new protein-binding interface through dimerization/oligomerization. Intriguingly, disruption of this interaction by point mutations abrogates AML1-ETO-induced haematopoietic stem/progenitor cell self-renewal and leukaemogenesis. These results reveal new mechanisms of action of AML1-ETO, and provide a potential therapeutic target in t(8;21)-positive acute myeloid leukaemia.