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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1252-1260
Number of pages9
JournalEpigenetics
Volume9
Issue number9
DOIs
Publication statusPublished - 2014

Keywords

  • DNA methylation
  • Epigenetics
  • JMML
  • juvenile myelomonocytic leukemia
  • RASA4

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Medicine(all)

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