融合蛋白AML1–ETO是“急性髓性白血病” (AML) 中最常见的染色体易位。在其中，造血转录因子AML1的“DNA-结合域”被融合到ETO蛋白的四个保守域 (NHR1–4) 中，这样所形成的组合蛋白与基因抑制和激发都有关。本文分析了白血病细胞中与内源AML1–ETO发生相互作用的各种不同蛋白，同时一个新识别出的蛋白结合界面被发现在白血病发生中起重要作用。（生物谷Bioon.com）
生物谷推荐的英文摘要
Nature doi:10.1038/nature12287
A stable transcription factor complex nucleated by oligomeric AML1–ETO controls leukaemogenesis
Xiao-Jian Sun, Zhanxin Wang, Lan Wang, Yanwen Jiang, Nils Kost, T. David Soong, Wei-Yi Chen, Zhanyun Tang, Tomoyoshi Nakadai, Olivier Elemento, Wolfgang Fischle, Ari Melnick, Dinshaw J. Patel, Stephen D. Nimer & Robert G. Roeder
Transcription factors are frequently altered in leukaemia through chromosomal translocation, mutation or aberrant expression1. 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 activation2. AML1–ETO oligomerization, mediated by the NHR2 domain, is critical for leukaemogenesis3, 4, 5, 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.