title: CREBBP is a target of epigenetic, but not genetic, modification in juvenile myelomonocytic leukemia.
abstract: 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.
  
  
  RESULTS
  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.
authors.affiliation: Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University Medical Center, Mathildenstrasse 1, 79106 Freiburg, Germany.|Hermann Staudinger Graduate School, University of Freiburg, Freiburg, Germany.
authors.forename: Silvia
authors.initials: S
authors.lastname: Fluhr
authors.affiliation: Institute of Molecular Medicine and Cell Research, University of Freiburg, Freiburg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Boerries
authors.affiliation: Institute of Molecular Medicine and Cell Research, University of Freiburg, Freiburg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Hauke
authors.initials: H
authors.lastname: Busch
authors.affiliation: Institute of Molecular Medicine and Cell Research, University of Freiburg, Freiburg, Germany.
authors.forename: Aikaterini
authors.initials: A
authors.lastname: Symeonidi
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Tania
authors.initials: T
authors.lastname: Witte
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Lipka
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Mücke
authors.affiliation: Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University Medical Center, Mathildenstrasse 1, 79106 Freiburg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nöllke
authors.affiliation: Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University Medical Center, Mathildenstrasse 1, 79106 Freiburg, Germany.
authors.forename: Christopher Felix
authors.initials: CF
authors.lastname: Krombholz
authors.affiliation: Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University Medical Center, Mathildenstrasse 1, 79106 Freiburg, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Charlotte M
authors.initials: CM
authors.lastname: Niemeyer
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg, Germany.|Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Plass
authors.affiliation: Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University Medical Center, Mathildenstrasse 1, 79106 Freiburg, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Flotho
mesh_terms: D050882:CREB-Binding Protein / Q000235:genetics*; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D006801:Humans; D054429:Leukemia, Myelomonocytic, Juvenile / Q000235:genetics* / Q000473:pathology*; D013058:Mass Spectrometry / Q000379:methods; D011379:Prognosis
chemical_list: D050882:CREB-Binding Protein; C494363:CREBBP protein, human
keywords: CREBBP; DNA methylation; Epigenetics; Juvenile myelomonocytic leukemia