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

作者: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*
来源:Nature, 2013, 500(7460): 93-U120.
DOI:10.1038/nature12287

摘要

Transcription factors are frequently altered in leukaemia through chromosomal translocation, mutation or aberrant . 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 %26apos;read%26apos; 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.

  • 出版日期2013-8-1