BACKGROUND: Nearly 15% of acute myeloid leukemia (AML) cases are caused by aberrant expression of AML1-ETO, a fusion protein generated by the t(8;21) chromosomal translocation. Since its discovery, AML1-ETO has served as a prototype to understand how leukemia fusion proteins deregulate transcription to promote leukemogenesis. Another leukemia fusion protein, E2A-Pbx1, generated by the t(1;19) translocation, is involved in acute lymphoblastic leukemias (ALLs). While AML1-ETO and E2A-Pbx1 are structurally unrelated fusion proteins, we have recently shown that a common axis, the ETO/E-protein interaction, is involved in the regulation of both fusion proteins, underscoring the importance of studying protein-protein interactions in elucidating the mechanisms of leukemia fusion proteins. OBJECTIVE: In this review, we aim to summarize these new developments while also providing a historic overview of the related early studies. METHODS: A total of 218 publications were reviewed in this article, a majority of which were published after 2004.We also downloaded 3D structures of AML1-ETO domains from Protein Data Bank and provided a systematic summary of their structures. RESULTS: By reviewing the literature, we summarized early and recent findings on AML1-ETO, including its protein-protein interactions, transcriptional and leukemogenic mechanisms, as well as the recently reported involvement of ETO family corepressors in regulating the function of E2A-Pbx1. CONCLUSION: While the recent development in genomic and structural studies has clearly demonstrated that the fusion proteins function by directly regulating transcription, a further understanding of the underlying mechanisms, including crosstalk with other transcription factors and cofactors, and the protein-protein interactions in the context of native proteins, may be necessary for the development of highly targeted drugs for leukemia therapy.
BACKGROUND: Nearly 15% of acute myeloid leukemia (AML) cases are caused by aberrant expression of AML1-ETO, a fusion protein generated by the t(8;21) chromosomal translocation. Since its discovery, AML1-ETO has served as a prototype to understand how leukemia fusion proteins deregulate transcription to promote leukemogenesis. Another leukemia fusion protein, E2A-Pbx1, generated by the t(1;19) translocation, is involved in acute lymphoblastic leukemias (ALLs). While AML1-ETO and E2A-Pbx1 are structurally unrelated fusion proteins, we have recently shown that a common axis, the ETO/E-protein interaction, is involved in the regulation of both fusion proteins, underscoring the importance of studying protein-protein interactions in elucidating the mechanisms of leukemia fusion proteins. OBJECTIVE: In this review, we aim to summarize these new developments while also providing a historic overview of the related early studies. METHODS: A total of 218 publications were reviewed in this article, a majority of which were published after 2004.We also downloaded 3D structures of AML1-ETO domains from Protein Data Bank and provided a systematic summary of their structures. RESULTS: By reviewing the literature, we summarized early and recent findings on AML1-ETO, including its protein-protein interactions, transcriptional and leukemogenic mechanisms, as well as the recently reported involvement of ETO family corepressors in regulating the function of E2A-Pbx1. CONCLUSION: While the recent development in genomic and structural studies has clearly demonstrated that the fusion proteins function by directly regulating transcription, a further understanding of the underlying mechanisms, including crosstalk with other transcription factors and cofactors, and the protein-protein interactions in the context of native proteins, may be necessary for the development of highly targeted drugs for leukemia therapy.
Authors: S Minucci; M Maccarana; M Cioce; P De Luca; V Gelmetti; S Segalla; L Di Croce; S Giavara; C Matteucci; A Gobbi; A Bianchini; E Colombo; I Schiavoni; G Badaracco; X Hu; M A Lazar; N Landsberger; C Nervi; P G Pelicci Journal: Mol Cell Date: 2000-05 Impact factor: 17.970
Authors: K L Rhoades; C J Hetherington; N Harakawa; D A Yergeau; L Zhou; L Q Liu; M T Little; D G Tenen; D E Zhang Journal: Blood Date: 2000-09-15 Impact factor: 22.113
Authors: A Ptasinska; S A Assi; D Mannari; S R James; D Williamson; J Dunne; M Hoogenkamp; M Wu; M Care; H McNeill; P Cauchy; M Cullen; R M Tooze; D G Tenen; B D Young; P N Cockerill; D R Westhead; O Heidenreich; C Bonifer Journal: Leukemia Date: 2012-02-20 Impact factor: 11.528
Authors: Kasper D Rasmussen; Guangshuai Jia; Jens V Johansen; Marianne T Pedersen; Nicolas Rapin; Frederik O Bagger; Bo T Porse; Olivier A Bernard; Jesper Christensen; Kristian Helin Journal: Genes Dev Date: 2015-04-17 Impact factor: 11.361