AML1-ETO 的白血病发生能力依赖于特定位点的赖氨酸乙酰化。
The leukemogenicity of AML1-ETO is dependent on site-specific lysine acetylation.
机构信息
Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
出版信息
Science. 2011 Aug 5;333(6043):765-9. doi: 10.1126/science.1201662. Epub 2011 Jul 14.
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.
摘要
在急性髓细胞白血病（AML）中发现的染色体易位产生具有异常转录调控特性的致癌融合转录因子。尽管大多数白血病融合蛋白的治疗靶向仍然难以捉摸，但控制其功能的翻译后修饰可能是可靶向的。我们发现，由 t(8;21)易位产生的融合蛋白 AML1-ETO 在来自 t(8;21) AML 患者的白血病细胞中被转录共激活因子 p300 乙酰化，并且这种乙酰化对于其在人脐带血 CD34(+)细胞中的自我更新促进作用及其在小鼠模型中的致白血病性是必不可少的。p300 的抑制消除了 AML1-ETO 的乙酰化，并损害了其促进白血病转化的能力。因此，赖氨酸乙酰转移酶在 AML 中代表了一个潜在的治疗靶点。
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