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Aberrant DNA methylation characterizes juvenile myelomonocytic leukemia with poor outcome.

Authors
  • Olk-Batz, Christiane
  • Poetsch, Anna R
  • Nöllke, Peter
  • Claus, Rainer
  • Zucknick, Manuela
  • Sandrock, Inga
  • Witte, Tania
  • Strahm, Brigitte
  • Hasle, Henrik
  • Zecca, Marco
  • Stary, Jan
  • Bergstraesser, Eva
  • De Moerloose, Barbara
  • Trebo, Monika
  • van den Heuvel-Eibrink, Marry M
  • Wojcik, Dorota
  • Locatelli, Franco
  • Plass, Christoph
  • Niemeyer, Charlotte M
  • Flotho, Christian
Type
Published Article
Journal
Blood
Publisher
American Society of Hematology
Publication Date
May 05, 2011
Volume
117
Issue
18
Pages
4871–4880
Identifiers
DOI: 10.1182/blood-2010-08-298968
PMID: 21406719
Source
Medline
License
Unknown

Abstract

Aberrant DNA methylation contributes to the malignant phenotype in virtually all types of cancer, including myeloid leukemia. We hypothesized that CpG island hypermethylation also occurs in juvenile myelomonocytic leukemia (JMML) and investigated whether it is associated with clinical, hematologic, or prognostic features. Based on quantitative measurements of DNA methylation in 127 JMML cases using mass spectrometry (MassARRAY), we identified 4 gene CpG islands with frequent hypermethylation: BMP4 (36% of patients), CALCA (54%), CDKN2B (22%), and RARB (13%). Hypermethylation was significantly associated with poor prognosis: when the methylation data were transformed into prognostic scores using a LASSO Cox regression model, the 5-year overall survival was 0.41 for patients in the top tertile of scores versus 0.72 in the lowest score tertile (P = .002). Among patients given allogeneic hematopoietic stem cell transplantation, the 5-year cumulative incidence of relapse was 0.52 in the highest versus 0.10 in the lowest score tertile (P = .007). In multivariate models, DNA methylation retained prognostic value independently of other clinical risk factors. Longitudinal analyses indicated that some cases acquired a more extensively methylated phenotype at relapse. In conclusion, our data suggest that a high-methylation phenotype characterizes an aggressive biologic variant of JMML and is an important molecular predictor of outcome.

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