|
|
Blood, 1 May 2007, Vol. 109, No. 9, pp. 3895-3905.
Prepublished online as a Blood First Edition Paper on January 18, 2007; DOI 10.1182/blood-2006-08-040147.
 Previous Article | Next Article 
Submitted August 10, 2006
Accepted December 26, 2006
The C/EBP tumor suppressor is silenced by
hypermethylation in acute myeloid leukemia
Shuchi Agrawal, Wolf-Karsten Hofmann, Nicola Tidow, Mathias Ehrich, Dirk van den Boom, Steffen Koschmieder, Wolfgang E. Berdel, Hubert Serve, and Carsten Muller-Tidow*
The Department of Medicine, Hematology and Oncology, University of Munster, Munster, Germany
The Department of Oncology and Hematology, University Hospital Benjamin Franklin, Berlin, Germany
Sequenom, San Diego, CA, United States
* Corresponding author; email: muellerc{at}uni-muenster.de.
Aberrant DNA methylation is the most frequent molecular alteration in acute myeloid leukemia. To identify methylation silenced genes in AML we performed microarray analyses in U937 cells exposed to the demethylating agent 5-Aza-deoxy-cytidine. Overall, 274 transcripts were significantly induced. Interestingly, C/EBP expression was significantly induced (>10 fold) by demethylation whereas, expression of all other C/EBP family members remained unchanged. The C/EBP promoter was strongly methylated in different leukemic cell lines and showed signs of a repressed chromatin state. Analyses of the promoter regions of the entire C/EBP family ( , , ,, , ) in bone marrow samples from AML patients (n=80) and controls (n=15) by mass spectrometry revealed that C/EBP is the most commonly hypermethylated C/EBP gene in AML. Hypermethylation occurred in more than 35% of AML patients at primary diagnosis. A significant correlation (p=0.016) was observed between hypermethylation of the C/EBP promoter and low expression of C/EBP in AML patients. C/EBP promoter activity was strongly repressed by methylation in vitro and transcriptional repression partially depended on MeCP2 activity. C/EBP exhibited growth-inhibitory properties in primary progenitor cells as well as in Flt3-ITD transformed cells. Taken together, C/EBP is a novel tumor suppressor gene in acute myeloid leukemia that is silenced by promoter methylation.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
C.-Y. Ko, H.-C. Hsu, M.-R. Shen, W.-C. Chang, and J.-M. Wang
Epigenetic Silencing of CCAAT/Enhancer-binding Protein {delta} Activity by YY1/Polycomb Group/DNA Methyltransferase Complex
J. Biol. Chem.,
November 7, 2008;
283(45):
30919 - 30932.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Kroeger, J. Jelinek, M. R. H. Estecio, R. He, K. Kondo, W. Chung, L. Zhang, L. Shen, H. M. Kantarjian, C. E. Bueso-Ramos, et al.
Aberrant CpG island methylation in acute myeloid leukemia is accentuated at relapse
Blood,
August 15, 2008;
112(4):
1366 - 1373.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Zhou, J. Si, T. Liu, and J. W. DeWille
PIASy Represses CCAAT/Enhancer-binding Protein {delta} (C/EBP{delta}) Transcriptional Activity by Sequestering C/EBP{delta} to the Nuclear Periphery
J. Biol. Chem.,
July 18, 2008;
283(29):
20137 - 20148.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Muller-Tidow and S. Koschmieder
The hidden faces of C/EBP{beta}
Blood,
March 15, 2008;
111(6):
2949 - 2950.
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. J. Wouters, M. A. Jorda, K. Keeshan, I. Louwers, C. A. J. Erpelinck-Verschueren, D. Tielemans, A. W. Langerak, Y. He, Y. Yashiro-Ohtani, P. Zhang, et al.
Distinct gene expression profiles of acute myeloid/T-lymphoid leukemia with silenced CEBPA and mutations in NOTCH1
Blood,
November 15, 2007;
110(10):
3706 - 3714.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
