A stable transcription factor complex nucleated by oligomeric AML1-ETO controls leukaemogenesis Journal Article
| Authors: | Sun, X. J.; Wang, Z.; Wang, L.; Jiang, Y.; Kost, N.; Soong, T. D.; Chen, W. Y.; Tang, Z.; Nakadai, T.; Elemento, O.; Fischle, W.; Melnick, A.; Patel, D. J.; Nimer, S. D.; Roeder, R. G. |
| Article Title: | A stable transcription factor complex nucleated by oligomeric AML1-ETO controls leukaemogenesis |
| Abstract: | 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. © 2013 Macmillan Publishers Limited. All rights reserved. |
| Keywords: | controlled study; acute granulocytic leukemia; human cell; mutation; leukemia, myeloid, acute; nonhuman; mouse; animals; mice; gene targeting; cell division; gene expression; animal experiment; animal model; protein; protein binding; protein stability; in vivo study; protein interaction; in vitro study; peptide; cell line, tumor; transcription factors; cell transformation, neoplastic; amino acid sequence; molecular sequence data; protein multimerization; leukemia cell; leukemogenesis; oncogene proteins, fusion; hematopoietic stem cells; genome; models, molecular; dimerization; protein structure, tertiary; multiprotein complexes; binding sites; hematopoietic stem cell; point mutation; dna binding; oligomerization; gene location; core binding factor alpha 2 subunit; amino acid motifs; transcription factor runx1; translocation; disease; crystallography |
| Journal Title: | Nature |
| Volume: | 500 |
| Issue: | 7460 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2013-08-01 |
| Start Page: | 93 |
| End Page: | 97 |
| Language: | English |
| DOI: | 10.1038/nature12287 |
| PROVIDER: | scopus |
| PMCID: | PMC3732535 |
| PUBMED: | 23812588 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 4 September 2013" - "CODEN: NATUA" - "Source: Scopus" |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work