| 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. |
| Keywords: |
unclassified drug; acute granulocytic leukemia; leukemia, myeloid, acute; chromosome; animals; mice; gene expression profiling; cell line; protein; protein binding; developmental biology; tumor cells, cultured; enzyme activity; cell line, tumor; mice, inbred c57bl; cell transformation, neoplastic; blood; fetal blood; protein processing; transcription regulation; protein processing, post-translational; hybrid protein; leukemogenesis; oncogene proteins, fusion; hematopoietic stem cells; chromosome translocation; amino acid; rodent; mutant proteins; transcriptional activation; protein interaction domains and motifs; cell organelle; lysine; core binding factor alpha 2 subunit; acetylation; transformation; transcription factor runx1; translocation; inhibition; protein p300; numerical model; acetylene; preleukemia; protein aml1 eto; e1a-associated p300 protein
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