Aberrant DNA methylation characterizes juvenile myelomonocytic leukemia with poor outcome

Christiane Olk-Batz, Anna R. Poetsch, Peter Nöllke, Rainer Claus, Manuela Zucknick, Inga Sandrock, Tania Witte, Brigitte Strahm, Henrik Hasle, Marco Zecca, Jan Starý, Eva Bergstraesser, Barbara De Moerloose, Monika Trebo, Marry M. Van Den Heuvel-Eibrink, Dorota Wojcik, Franco Locatelli, Christoph Plass, Charlotte M. Niemeyer, Christian Flotho

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)4871-4880
Number of pages10
JournalBlood
Volume117
Issue number18
DOIs
Publication statusPublished - May 5 2011

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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    Olk-Batz, C., Poetsch, A. R., Nöllke, P., Claus, R., Zucknick, M., Sandrock, I., Witte, T., Strahm, B., Hasle, H., Zecca, M., Starý, J., Bergstraesser, E., De Moerloose, B., Trebo, M., Van Den Heuvel-Eibrink, M. M., Wojcik, D., Locatelli, F., Plass, C., Niemeyer, C. M., & Flotho, C. (2011). Aberrant DNA methylation characterizes juvenile myelomonocytic leukemia with poor outcome. Blood, 117(18), 4871-4880. https://doi.org/10.1182/blood-2010-08-298968