The leukemogenicity of AML1-ETO is dependent on site-specific lysine acetylation

Lan Wang; Alexander Gural; Xiao Jian Sun; Xinyang Zhao; Fabiana Perna; Gang Huang; Megan A. Hatlen; Ly Vu; Fan Liu; Haiming Xu; Takashi Asai; Hao Xu; Tony Deblasio; Silvia Menendez; Francesca Voza; Yanwen Jiang; Philip A. Cole; Jinsong Zhang; Ari Melnick; Robert G. Roeder; Stephen D. Nimer

doi:10.1126/science.1201662

The leukemogenicity of AML1-ETO is dependent on site-specific lysine acetylation

Lan Wang, Alexander Gural, Xiao Jian Sun, Xinyang Zhao, Fabiana Perna, Gang Huang, Megan A. Hatlen, Ly Vu, Fan Liu, Haiming Xu, Takashi Asai, Hao Xu, Tony Deblasio, Silvia Menendez, Francesca Voza, Yanwen Jiang, Philip A. Cole, Jinsong Zhang, Ari Melnick, Robert G. RoederStephen D. Nimer^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

188 Scopus citations

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.

Original language	English
Pages (from-to)	765-769
Number of pages	5
Journal	Science
Volume	333
Issue number	6043
DOIs	https://doi.org/10.1126/science.1201662
State	Published - 5 Aug 2011
Externally published	Yes

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Wang, L., Gural, A., Sun, X. J., Zhao, X., Perna, F., Huang, G., Hatlen, M. A., Vu, L., Liu, F., Xu, H., Asai, T., Xu, H., Deblasio, T., Menendez, S., Voza, F., Jiang, Y., Cole, P. A., Zhang, J., Melnick, A., ... Nimer, S. D. (2011). The leukemogenicity of AML1-ETO is dependent on site-specific lysine acetylation. Science, 333(6043), 765-769. https://doi.org/10.1126/science.1201662

@article{6f34c4ae48814e2591ae94be7e4d457d,

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.",

author = "Lan Wang and Alexander Gural and Sun, {Xiao Jian} and Xinyang Zhao and Fabiana Perna and Gang Huang and Hatlen, {Megan A.} and Ly Vu and Fan Liu and Haiming Xu and Takashi Asai and Hao Xu and Tony Deblasio and Silvia Menendez and Francesca Voza and Yanwen Jiang and Cole, {Philip A.} and Jinsong Zhang and Ari Melnick and Roeder, {Robert G.} and Nimer, {Stephen D.}",

year = "2011",

month = aug,

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doi = "10.1126/science.1201662",

language = "אנגלית",

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Wang, L, Gural, A, Sun, XJ, Zhao, X, Perna, F, Huang, G, Hatlen, MA, Vu, L, Liu, F, Xu, H, Asai, T, Xu, H, Deblasio, T, Menendez, S, Voza, F, Jiang, Y, Cole, PA, Zhang, J, Melnick, A, Roeder, RG & Nimer, SD 2011, 'The leukemogenicity of AML1-ETO is dependent on site-specific lysine acetylation', Science, vol. 333, no. 6043, pp. 765-769. https://doi.org/10.1126/science.1201662

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T1 - The leukemogenicity of AML1-ETO is dependent on site-specific lysine acetylation

AU - Wang, Lan

AU - Gural, Alexander

AU - Sun, Xiao Jian

AU - Zhao, Xinyang

AU - Perna, Fabiana

AU - Huang, Gang

AU - Hatlen, Megan A.

AU - Vu, Ly

AU - Liu, Fan

AU - Xu, Haiming

AU - Asai, Takashi

AU - Xu, Hao

AU - Deblasio, Tony

AU - Menendez, Silvia

AU - Voza, Francesca

AU - Jiang, Yanwen

AU - Cole, Philip A.

AU - Zhang, Jinsong

AU - Melnick, Ari

AU - Roeder, Robert G.

AU - Nimer, Stephen D.

PY - 2011/8/5

Y1 - 2011/8/5

N2 - 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.

AB - 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.

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The leukemogenicity of AML1-ETO is dependent on site-specific lysine acetylation

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