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Aberrant DNA methylation characterizes juvenile myelomonocytic leukemia with poor outcome

(2011) BLOOD. 117(18). p.4871-4880
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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.
Keywords
TRANSPLANTATION, CHILDREN, RAS MUTATIONS, RETROSPECTIVE ANALYSIS, MYELODYSPLASTIC SYNDROME, CHRONIC MYELOGENOUS LEUKEMIA, ACUTE MYELOID-LEUKEMIA, CELLS, SURVIVAL, CANCER

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Chicago
Olk-Batz, Christiane, Anna R Poetsch, Peter Nöllke, Rainer Claus, Manuela Zucknick, Inga Sandrock, Tania Witte, et al. 2011. “Aberrant DNA Methylation Characterizes Juvenile Myelomonocytic Leukemia with Poor Outcome.” Blood 117 (18): 4871–4880.
APA
Olk-Batz, C., Poetsch, A. R., Nöllke, P., Claus, R., Zucknick, M., Sandrock, I., Witte, T., et al. (2011). Aberrant DNA methylation characterizes juvenile myelomonocytic leukemia with poor outcome. BLOOD, 117(18), 4871–4880.
Vancouver
1.
Olk-Batz C, Poetsch AR, Nöllke P, Claus R, Zucknick M, Sandrock I, et al. Aberrant DNA methylation characterizes juvenile myelomonocytic leukemia with poor outcome. BLOOD. 2011;117(18):4871–80.
MLA
Olk-Batz, Christiane, Anna R Poetsch, Peter Nöllke, et al. “Aberrant DNA Methylation Characterizes Juvenile Myelomonocytic Leukemia with Poor Outcome.” BLOOD 117.18 (2011): 4871–4880. Print.
@article{1199681,
  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.},
  author       = {Olk-Batz, Christiane and Poetsch, Anna R and N{\"o}llke, Peter and Claus, Rainer and Zucknick, Manuela and Sandrock, Inga and Witte, Tania and Strahm, Brigitte and Hasle, Henrik and Zecca, Marco and Stary, Jan and Bergstraesser, Eva  and De Moerloose, Barbara and Trebo, Monika and Van Den Heuvel-Eibrink, Mary M and Wojcik, Dorota and Locatelli, Franco and Plass, Christoph and Niemeyer, Charlotte M. and Flotho, Christian},
  issn         = {0006-4971},
  journal      = {BLOOD},
  keyword      = {TRANSPLANTATION,CHILDREN,RAS MUTATIONS,RETROSPECTIVE ANALYSIS,MYELODYSPLASTIC SYNDROME,CHRONIC MYELOGENOUS LEUKEMIA,ACUTE MYELOID-LEUKEMIA,CELLS,SURVIVAL,CANCER},
  language     = {eng},
  number       = {18},
  pages        = {4871--4880},
  title        = {Aberrant DNA methylation characterizes juvenile myelomonocytic leukemia with poor outcome},
  url          = {http://dx.doi.org/10.1182/blood-2010-08-298968},
  volume       = {117},
  year         = {2011},
}

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