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  • 1
    Publication Date: 2013-07-03
    Description: Transcription factors are frequently altered in leukaemia through chromosomal translocation, mutation or aberrant expression. 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. AML1-ETO oligomerization, mediated by the NHR2 domain, is critical for leukaemogenesis, making it important to identify co-regulatory factors that 'read' the NHR2 oligomerization and contribute to leukaemogenesis. 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.〈br /〉〈br /〉〈a href="" target="_blank"〉〈img src="" border="0"〉〈/a〉   〈a href="" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sun, Xiao-Jian -- Wang, Zhanxin -- Wang, Lan -- Jiang, Yanwen -- Kost, Nils -- Soong, T David -- Chen, Wei-Yi -- Tang, Zhanyun -- Nakadai, Tomoyoshi -- Elemento, Olivier -- Fischle, Wolfgang -- Melnick, Ari -- Patel, Dinshaw J -- Nimer, Stephen D -- Roeder, Robert G -- CA113872/CA/NCI NIH HHS/ -- CA129325/CA/NCI NIH HHS/ -- CA163086/CA/NCI NIH HHS/ -- CA166835/CA/NCI NIH HHS/ -- R01 CA163086/CA/NCI NIH HHS/ -- R01 CA166835/CA/NCI NIH HHS/ -- UL1 RR024143/RR/NCRR NIH HHS/ -- UL1RR024143/RR/NCRR NIH HHS/ -- England -- Nature. 2013 Aug 1;500(7460):93-7. doi: 10.1038/nature12287. Epub 2013 Jun 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Amino Acid Sequence ; Animals ; Binding Sites ; Cell Division ; Cell Line, Tumor ; *Cell Transformation, Neoplastic/genetics ; Core Binding Factor Alpha 2 Subunit/chemistry/*metabolism ; Hematopoietic Stem Cells/cytology/metabolism/pathology ; Humans ; Leukemia, Myeloid, Acute/genetics/*metabolism/*pathology ; Mice ; Models, Molecular ; Molecular Sequence Data ; Multiprotein Complexes/chemistry/*metabolism ; Oncogene Proteins, Fusion/chemistry/*metabolism ; Point Mutation ; Protein Binding ; Protein Multimerization ; Protein Stability ; Protein Structure, Tertiary ; Transcription Factors/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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