CREBBP is a target of epigenetic, but not genetic, modification in juvenile myelomonocytic leukemia.
Silvia Fluhr, Melanie Boerries, Hauke Busch, Aikaterini Symeonidi, Tania Witte, Daniel B Lipka, Oliver Mücke, Peter Nöllke, Christopher Felix Krombholz, Charlotte M Niemeyer, Christoph Plass, Christian Flotho
Author Information
Silvia Fluhr: Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University Medical Center, Mathildenstrasse 1, 79106 Freiburg, Germany.
Melanie Boerries: Institute of Molecular Medicine and Cell Research, University of Freiburg, Freiburg, Germany.
Hauke Busch: Institute of Molecular Medicine and Cell Research, University of Freiburg, Freiburg, Germany.
Aikaterini Symeonidi: Institute of Molecular Medicine and Cell Research, University of Freiburg, Freiburg, Germany.
Tania Witte: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center, Heidelberg, Germany.
Daniel B Lipka: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center, Heidelberg, Germany.
Oliver Mücke: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center, Heidelberg, Germany.
Peter Nöllke: Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University Medical Center, Mathildenstrasse 1, 79106 Freiburg, Germany.
Christopher Felix Krombholz: Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University Medical Center, Mathildenstrasse 1, 79106 Freiburg, Germany.
Charlotte M Niemeyer: Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University Medical Center, Mathildenstrasse 1, 79106 Freiburg, Germany.
Christoph Plass: German Cancer Consortium (DKTK), Heidelberg, Germany.
Christian Flotho: Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University Medical Center, Mathildenstrasse 1, 79106 Freiburg, Germany.
BACKGROUND: Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative neoplasm of childhood whose clinical heterogeneity is only poorly represented by gene sequence alterations. It was previously shown that aberrant DNA methylation of distinct target genes defines a more aggressive variant of JMML, but only few significant targets are known so far. To get a broader picture of disturbed CpG methylation patterns in JMML, we carried out a methylation screen of 34 candidate genes in 45 patients using quantitative mass spectrometry. FINDINGS: Five of 34 candidate genes analyzed showed recurrent hypermethylation in JMML. cAMP-responsive element-binding protein-binding protein (CREBBP) was the most frequent target of epigenetic modification (77 % of cases). However, no pathogenic mutations of CREBBP were identified in a genetic analysis of 64 patients. CREBBP hypermethylation correlated with clinical parameters known to predict poor outcome. CONCLUSIONS: This study supports the relevance of epigenetic aberrations in JMML pathophysiology. Our data confirm that DNA hypermethylation in JMML is highly target-specific and associated with higher-risk features. These findings encourage the development of prognostic markers based on epigenetic alterations, which will be helpful in the difficult clinical management of this heterogeneous disease.
