|
|
Blood, 5 February 2009, Vol. 113, No. 6, pp. 1315-1325.
Prepublished online as a Blood First Edition Paper on October 2, 2008November 20, 2008; DOI 10.1182/blood-2008-06-163246.
 Previous Article | Next Article 
Submitted June 16, 2008
Accepted September 8, 2008
Aberrant DNA methylation is a dominant mechanism in
MDS progression to AML
Ying Jiang, Andrew Dunbar, Lukasz P. Gondek, Sanjay Mohan, Manjot Rataul, Christine O'Keefe, Mikkael Sekeres, Yogen Saunthararajah, and Jaroslaw P. Maciejewski*
Experimental Hematology and Hematopoiesis Section, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, United States
Department of Hematologic Oncology and Blood Disorders, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, United States
* Corresponding author; email: maciejj{at}ccf.org.
Myelodysplastic syndromes (MDS) are clonal hematological disorders that frequently represent an intermediate disease stage before progression to acute myeloid leukemia (AML). As such, study of MDS/AML can provide insight into the mechanisms of neoplastic evolution. In 184 MDS and AML patients, DNA methylation microarray and high-density SNP-A karyotyping were used to assess the relative contributions of aberrant DNA methylation and chromosomal deletions to tumor-suppressor gene (TSG) silencing during disease progression. Aberrant methylation was seen in every sample, on average affecting 91/1505 CpG loci in early MDS and 179/1505 loci after blast transformation (RAEB/AML). In contrast, chromosome aberrations were seen in 79% of early MDS samples, 90% of RAEB/AML samples, and were not as widely distributed over the genome. Analysis of the most frequently aberrantly methylated genes identified FZD9 as a candidate TSG on chromosome 7. In patients with chromosome deletion at the FZD9 locus, aberrant methylation of the remaining allele was associated with the poorest clinical outcome. These results indicate that aberrant methylation can cooperate with chromosome deletions to silence TSG. However, the ubiquity, extent and correlation with disease progression suggest that aberrant DNA methylation is the dominant source of TSG silencing and clonal variation in MDS evolution to AML.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
A. Tefferi and J. W. Vardiman
Myelodysplastic Syndromes
N. Engl. J. Med.,
November 5, 2009;
361(19):
1872 - 1885.
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. E. Figueroa, L. Skrabanek, Y. Li, A. Jiemjit, T. E. Fandy, E. Paietta, H. Fernandez, M. S. Tallman, J. M. Greally, H. Carraway, et al.
MDS and secondary AML display unique patterns and abundance of aberrant DNA methylation
Blood,
October 15, 2009;
114(16):
3448 - 3458.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
O. Kosmider, V. Gelsi-Boyer, M. Cheok, S. Grabar, V. Della-Valle, F. Picard, F. Viguie, B. Quesnel, O. Beyne-Rauzy, E. Solary, et al.
TET2 mutation is an independent favorable prognostic factor in myelodysplastic syndromes (MDSs)
Blood,
October 8, 2009;
114(15):
3285 - 3291.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Y. Follo, C. Finelli, S. Mongiorgi, C. Clissa, C. Bosi, N. Testoni, F. Chiarini, G. Ramazzotti, M. Baccarani, A. M. Martelli, et al.
Reduction of phosphoinositide-phospholipase C beta1 methylation predicts the responsiveness to azacitidine in high-risk MDS
PNAS,
September 29, 2009;
106(39):
16811 - 16816.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. M. Jankowska, H. Szpurka, R. V. Tiu, H. Makishima, M. Afable, J. Huh, C. L. O'Keefe, R. Ganetzky, M. A. McDevitt, and J. P. Maciejewski
Loss of heterozygosity 4q24 and TET2 mutations associated with myelodysplastic/myeloproliferative neoplasms
Blood,
June 18, 2009;
113(25):
6403 - 6410.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. I. Martin-Subero, M. Kreuz, M. Bibikova, S. Bentink, O. Ammerpohl, E. Wickham-Garcia, M. Rosolowski, J. Richter, L. Lopez-Serra, E. Ballestar, et al.
New insights into the biology and origin of mature aggressive B-cell lymphomas by combined epigenomic, genomic, and transcriptional profiling
Blood,
March 12, 2009;
113(11):
2488 - 2497.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
