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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, et al. (2011) BLOOD. 117(18). p.4871-4880
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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
TRANSPLANTATION, CHILDREN, RAS MUTATIONS, RETROSPECTIVE ANALYSIS, MYELODYSPLASTIC SYNDROME, CHRONIC MYELOGENOUS LEUKEMIA, ACUTE MYELOID-LEUKEMIA, CELLS, SURVIVAL, CANCER
journal title
BLOOD
Blood
volume
117
issue
18
pages
4871 - 4880
Web of Science type
Article
Web of Science id
000290275700031
JCR category
HEMATOLOGY
JCR impact factor
9.898 (2011)
JCR rank
2/68 (2011)
JCR quartile
1 (2011)
ISSN
0006-4971
DOI
10.1182/blood-2010-08-298968
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
1199681
handle
http://hdl.handle.net/1854/LU-1199681
date created
2011-03-30 16:21:49
date last changed
2016-12-19 15:45:12
@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},
}

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.