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Blood, 15 August 2008, Vol. 112, No. 4, pp. 1366-1373.
Prepublished online as a Blood First Edition Paper on June 3, 2008; DOI 10.1182/blood-2007-11-126227.
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Submitted November 30, 2007
Accepted April 21, 2008
Aberrant CpG island methylation in acute myeloid leukemia is accentuated at relapse
Heike Kroeger, Jaroslav Jelinek, Marcos R. H. Estecio, Rong He, Kimie Kondo, Woonbok Chung, Li Zhang, Lanlan Shen, Hagop M. Kantarjian, Carlos E. Bueso-Ramos, and Jean-Pierre J. Issa*
Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States
Department of Bioinformatics and Computational Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States
Department of Hematopathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States
* Corresponding author; email: jpissa{at}mdanderson.org.
DNA methylation of CpG islands around gene transcription start sites results in gene silencing and plays a role in leukemia pathophysiology. Its impact in leukemia progression is not fully understood. We performed genome-wide screening for methylated CpG islands and identified 8 genes frequently methylated in leukemia cell lines and in acute myeloid leukemia (AML) patients: NOR1, CDH13, p15, NPM2, OLIG2, PGR, HIN1, and SLC26A4. We assessed the methylation status of these genes and of the repetitive element LINE1 in 30 patients with AML, both at diagnosis and relapse. Abnormal methylation was found in 23%-83% of patients at diagnosis and in 47%-93% at relapse, with CDH13 being the most frequently methylated. We observed concordance in methylation of several genes, confirming the presence of a hypermethylator pathway in AML. DNA methylation levels increased at relapse in 25 of 30 (83%) AML patients. These changes represent much larger epigenetic dysregulation, since methylation microarray analysis of 9008 autosomal genes in 4 patients showed hypermethylation ranging from 5.9% to 13.6 % (median 8.3%) genes at diagnosis and 8.0% to 15.2% (median 10.6%) genes in relapse (P<.0001). Our data suggest that DNA methylation is involved in AML progression and provide a rationale for the use of epigenetic agents in remission maintenance.
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