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Epigenetics
Sep, 2014;9 (9): 1252-60.

RASA4 undergoes DNA hypermethylation in resistant juvenile myelomonocytic leukemia.

Anna R Poetsch, Daniel B Lipka, Tania Witte, Rainer Claus, Peter Nöllke, Manuela Zucknick, Christiane Olk-Batz, Silvia Fluhr, Michael Dworzak, Barbara De Moerloose, Jan Starý, Marco Zecca, Henrik Hasle, Markus Schmugge, Marry M van den Heuvel-Eibrink, Franco Locatelli, Charlotte M Niemeyer, Christian Flotho, Christoph Plass
Author Information
  1. Anna R Poetsch: Division of Epigenomics and Cancer Risk Factors (C010); German Cancer Research Center; Heidelberg, Germany.
  2. Daniel B Lipka: Division of Epigenomics and Cancer Risk Factors (C010); German Cancer Research Center; Heidelberg, Germany.
  3. Tania Witte: Division of Epigenomics and Cancer Risk Factors (C010); German Cancer Research Center; Heidelberg, Germany.
  4. Rainer Claus: Division of Epigenomics and Cancer Risk Factors (C010); German Cancer Research Center; Heidelberg, Germany.
  5. Peter Nöllke: Division of Pediatric Hematology-Oncology; University Medical Center; Freiburg, Germany.
  6. Manuela Zucknick: Division of Biostatistics; German Cancer Research Center; Heidelberg, Germany.
  7. Christiane Olk-Batz: Division of Pediatric Hematology-Oncology; University Medical Center; Freiburg, Germany.
  8. Silvia Fluhr: Division of Pediatric Hematology-Oncology; University Medical Center; Freiburg, Germany.
  9. Michael Dworzak: St. Anna Children's Hospital and Children's Cancer Research Institute; Department of Pediatrics; Medical University of Vienna; Vienna, Austria.
  10. Barbara De Moerloose: Dept. of Pediatric Hematology-Oncology; Ghent University Hospital; Ghent, Belgium.
  11. Jan Starý: 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.
  12. Marco Zecca: Pediatric Hematology-Oncology; Fondazione IRCCS;Policlinico San Matteo; Pavia, Italy.
  13. Henrik Hasle: Department of Pediatrics; Aarhus University Hospital Skejby; Aarhus, Denmark.
  14. Markus Schmugge: Division of Hematology; University Children's Hospital; Zurich, Switzerland.
  15. Marry M van den Heuvel-Eibrink: Department of Pediatric Oncology-Hematology; Erasmus Medical Center; Rotterdam, The Netherlands; Dutch Children's Oncology Group; The Hague, Netherlands.
  16. Franco Locatelli: Department of Pediatric Hematology-Oncology; IRCCS Ospedale Bambino Gesu; Rome, Italy; University of Pavia; Pavia, Italy.
  17. Charlotte M Niemeyer: The German Cancer Consortium; Heidelberg, Germany; Division of Pediatric Hematology-Oncology; University Medical Center; Freiburg, Germany.
  18. Christian Flotho: The German Cancer Consortium; Heidelberg, Germany; Division of Pediatric Hematology-Oncology; University Medical Center; Freiburg, Germany.
  19. Christoph Plass: Division of Epigenomics and Cancer Risk Factors (C010); German Cancer Research Center; Heidelberg, Germany; The German Cancer Consortium; Heidelberg, Germany.
PMID: 25147919 DOI: 10.4161/epi.29941

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.

Keywords

JMML RASA4 epigenetics,juvenile myelomonocytic leukemia

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MeSH Term

Adolescent
Child
Child, Preschool
Chromosomes, Human, Pair 7
CpG Islands
DNA Methylation
Drug Resistance, Neoplasm
Female
Gene Silencing
Humans
Infant
Leukemia, Myelomonocytic, Juvenile
Male
Monosomy
Mutation
Prognosis
Promoter Regions, Genetic
Protein Isoforms
Protein Tyrosine Phosphatase, Non-Receptor Type 11
ras GTPase-Activating Proteins

Chemicals

Protein Isoforms
RASA4 protein, human
ras GTPase-Activating Proteins
PTPN11 protein, human
Protein Tyrosine Phosphatase, Non-Receptor Type 11
Journal Article Research Support, Non-U.S. Gov't
Article has an altmetric score of 1

Word Cloud

Created with Highcharts 10.0.0JMMLRASA4DNAmethylationjuvenilemyelomonocyticleukemiaisoform2hypermethylationpoorprognosis7proteinstransplantationcasesAberrantspecificgeneticlocikeymolecularfeatureUsingquantitativehigh-resolutionmassspectrometryidentifiedmapschromosomeencodesmemberGAP1familyGTPase-activatingsmallGrecurrenttargetisoform-specific51%125patientsanalyzedpromotercorrelatedclinicalparameterspredictingolderageelevatedfetalhemoglobinhigherriskrelapsehematopoieticstemcellPTPN11mutationlevelincreasedrelapsedInterestinglymonosomyexhibitedremainingalleleresultscorroboratesignificanceepigeneticmodificationsphenotypeaggressiveundergoesresistantepigenetics

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