The Leukemogenicity of AML1-ETO Is Dependent on Site-Specific Lysine Acetylation

• Published in: Science (American Association for the Advancement of Science) Vol. 333; no. 6043; pp. 765 - 769
• Main Authors: Wang, Lan, Gural, Alexander, Sun, Xiao-Jian, Zhao, Xinyang, Perna, Fabiana, Huang, Gang, Hatlen, Megan A., Vu, Ly, Liu, Fan, Xu, Haiming, Asai, Takashi, Xu, Hao, Deblasio, Tony, Menendez, Silvia, Voza, Francesca, Jiang, Yanwen, Cole, Philip A., Zhang, Jinsong, Melnick, Ari, Roeder, Robert G., Nimer, Stephen D.
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 05.08.2011; The American Association for the Advancement of Science
• Subjects: Acetylation; acetyltransferases; Amino acids; animal models; Animals; Antibodies; Biochemistry; Blood; Cell growth; Cell Line; Cell Line, Tumor; Cell Transformation, Neoplastic; Cells; Cellular biology; chromosome translocation; Chromosomes; Core Binding Factor Alpha 2 Subunit - chemistry; Core Binding Factor Alpha 2 Subunit - metabolism; E1A-Associated p300 Protein - antagonists & inhibitors; E1A-Associated p300 Protein - metabolism; Fetal Blood - cytology; Gene Expression Profiling; Genes; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - physiology; Histones; Humans; Leukemia; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; Leukemias; Leukocytes; Lysine; Lysine - metabolism; Mathematical models; Mice; Mice, Inbred C57BL; Mutant Proteins - metabolism; Myeloid leukemia; neoplasm cells; Oncogene Proteins, Fusion - chemistry; Oncogene Proteins, Fusion - metabolism; patients; post-translational modification; Preleukemia - metabolism; Preleukemia - pathology; Protein Binding; Protein Interaction Domains and Motifs; Protein Processing, Post-Translational; Proteins; Rope; RUNX1 Translocation Partner 1 Protein; transcription (genetics); transcription factors; Transcriptional Activation; Transformations; Translocation; Tumor Cells, Cultured
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.1201662

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.