title: The leukemogenicity of AML1-ETO is dependent on site-specific lysine acetylation.
abstract: The chromosomal translocations found in acute myelogenous leukemia (AML) generate oncogenic fusion transcription factors with aberrant transcriptional regulatory properties. Although therapeutic targeting of most leukemia fusion proteins remains elusive, the posttranslational modifications that control their function could be targetable. We found that AML1-ETO, the fusion protein generated by the t(8;21) translocation, is acetylated by the transcriptional coactivator p300 in leukemia cells isolated from t(8;21) AML patients, and that this acetylation is essential for its self-renewal-promoting effects in human cord blood CD34(+) cells and its leukemogenicity in mouse models. Inhibition of p300 abrogates the acetylation of AML1-ETO and impairs its ability to promote leukemic transformation. Thus, lysine acetyltransferases represent a potential therapeutic target in AML.
authors.affiliation: Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Wang
authors.forename: Alexander
authors.initials: A
authors.lastname: Gural
authors.forename: Xiao-Jian
authors.initials: XJ
authors.lastname: Sun
authors.forename: Xinyang
authors.initials: X
authors.lastname: Zhao
authors.forename: Fabiana
authors.initials: F
authors.lastname: Perna
authors.forename: Gang
authors.initials: G
authors.lastname: Huang
authors.forename: Megan A
authors.initials: MA
authors.lastname: Hatlen
authors.forename: Ly
authors.initials: L
authors.lastname: Vu
authors.forename: Fan
authors.initials: F
authors.lastname: Liu
authors.forename: Haiming
authors.initials: H
authors.lastname: Xu
authors.forename: Takashi
authors.initials: T
authors.lastname: Asai
authors.forename: Hao
authors.initials: H
authors.lastname: Xu
authors.forename: Tony
authors.initials: T
authors.lastname: Deblasio
authors.forename: Silvia
authors.initials: S
authors.lastname: Menendez
authors.forename: Francesca
authors.initials: F
authors.lastname: Voza
authors.forename: Yanwen
authors.initials: Y
authors.lastname: Jiang
authors.forename: Philip A
authors.initials: PA
authors.lastname: Cole
authors.forename: Jinsong
authors.initials: J
authors.lastname: Zhang
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
authors.forename: Robert G
authors.initials: RG
authors.lastname: Roeder
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Nimer
mesh_terms: D000107:Acetylation; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D050676:Core Binding Factor Alpha 2 Subunit / Q000737:chemistry / Q000378:metabolism*; D050881:E1A-Associated p300 Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005312:Fetal Blood / Q000166:cytology; D020869:Gene Expression Profiling; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000502:physiology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000473:pathology; D008239:Lysine / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D050505:Mutant Proteins / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000737:chemistry / Q000378:metabolism*; D011289:Preleukemia / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D011499:Protein Processing, Post-Translational; D000075142:RUNX1 Translocation Partner 1 Protein; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
chemical_list: C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D050505:Mutant Proteins; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D008239:Lysine