title: RASA4 undergoes DNA hypermethylation in resistant juvenile myelomonocytic leukemia.
abstract: Aberrant DNA methylation at specific genetic loci is a key molecular feature of juvenile myelomonocytic leukemia (JMML) with poor prognosis. Using quantitative high-resolution mass spectrometry, we identified RASA4 isoform 2, which maps to chromosome 7 and encodes a member of the GAP1 family of GTPase-activating proteins for small G proteins, as a recurrent target of isoform-specific DNA hypermethylation in JMML (51% of 125 patients analyzed). RASA4 isoform 2 promoter methylation correlated with clinical parameters predicting poor prognosis (older age, elevated fetal hemoglobin), with higher risk of relapse after hematopoietic stem cell transplantation, and with PTPN11 mutation. The level of isoform 2 methylation increased in relapsed cases after transplantation. Interestingly, most JMML cases with monosomy 7 exhibited hypermethylation on the remaining RASA4 allele. The results corroborate the significance of epigenetic modifications in the phenotype of aggressive JMML.
authors.affiliation: Division of Epigenomics and Cancer Risk Factors (C010); German Cancer Research Center; Heidelberg, Germany.
authors.forename: Anna R
authors.initials: AR
authors.lastname: Poetsch
authors.affiliation: Division of Epigenomics and Cancer Risk Factors (C010); 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 (C010); German Cancer Research Center; Heidelberg, Germany.
authors.forename: Tania
authors.initials: T
authors.lastname: Witte
authors.affiliation: Division of Epigenomics and Cancer Risk Factors (C010); German Cancer Research Center; Heidelberg, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Claus
authors.affiliation: Division of Pediatric Hematology-Oncology; University Medical Center; Freiburg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nöllke
authors.affiliation: Division of Biostatistics; German Cancer Research Center; Heidelberg, Germany.
authors.forename: Manuela
authors.initials: M
authors.lastname: Zucknick
authors.affiliation: Division of Pediatric Hematology-Oncology; University Medical Center; Freiburg, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Olk-Batz
authors.affiliation: Division of Pediatric Hematology-Oncology; University Medical Center; Freiburg, Germany.
authors.forename: Silvia
authors.initials: S
authors.lastname: Fluhr
authors.affiliation: St. Anna Children's Hospital and Children's Cancer Research Institute; Department of Pediatrics; Medical University of Vienna; Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Dworzak
authors.affiliation: Dept. of Pediatric Hematology-Oncology; Ghent University Hospital; Ghent, Belgium.
authors.forename: Barbara
authors.initials: B
authors.lastname: De Moerloose
authors.affiliation: Dept. of Pediatric Hematology and Oncology; 2nd Faculty of Medicine; Charles University and University Hospital Motol, Praha; Czech Pediatric Hematology Working Group (CPH); Prague, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Starý
authors.affiliation: Pediatric Hematology-Oncology; Fondazione IRCCS;Policlinico San Matteo; Pavia, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Zecca
authors.affiliation: Department of Pediatrics; Aarhus University Hospital Skejby; Aarhus, Denmark.
authors.forename: Henrik
authors.initials: H
authors.lastname: Hasle
authors.affiliation: Division of Hematology; University Children's Hospital; Zurich, Switzerland.
authors.forename: Markus
authors.initials: M
authors.lastname: Schmugge
authors.affiliation: Department of Pediatric Oncology-Hematology; Erasmus Medical Center; Rotterdam, The Netherlands; Dutch Children's Oncology Group; The Hague, Netherlands.
authors.forename: Marry M
authors.initials: MM
authors.lastname: van den Heuvel-Eibrink
authors.affiliation: Department of Pediatric Hematology-Oncology; IRCCS Ospedale Bambino Gesu; Rome, Italy; University of Pavia; Pavia, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Locatelli
authors.affiliation: The German Cancer Consortium; Heidelberg, Germany; Division of Pediatric Hematology-Oncology; University Medical Center; Freiburg, Germany.
authors.forename: Charlotte M
authors.initials: CM
authors.lastname: Niemeyer
authors.affiliation: The German Cancer Consortium; Heidelberg, Germany; Division of Pediatric Hematology-Oncology; University Medical Center; Freiburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Flotho
authors.affiliation: Division of Epigenomics and Cancer Risk Factors (C010); German Cancer Research Center; Heidelberg, Germany; The German Cancer Consortium; Heidelberg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Plass
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D002897:Chromosomes, Human, Pair 7; D018899:CpG Islands; D019175:DNA Methylation; D019008:Drug Resistance, Neoplasm; D005260:Female; D020868:Gene Silencing; D006801:Humans; D007223:Infant; D054429:Leukemia, Myelomonocytic, Juvenile / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009006:Monosomy; D009154:Mutation; D011379:Prognosis; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics / Q000378:metabolism; D020703:ras GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; C491144:RASA4 protein, human; D020703:ras GTPase-Activating Proteins; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11
keywords: JMML; RASA4; epigenetics,juvenile myelomonocytic leukemia