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.

• MeSH
• Drug Resistance, Neoplasm * MeSH
• CpG Islands MeSH
• Child MeSH
• Leukemia, Myelomonocytic, Juvenile diagnosis   metabolism   pathology   MeSH
• Infant MeSH
• Humans MeSH
• Chromosomes, Human, Pair 7 MeSH
• DNA Methylation * MeSH
• Adolescent MeSH
• Monosomy MeSH
• Mutation MeSH
• Child, Preschool MeSH
• Prognosis MeSH
• Promoter Regions, Genetic MeSH
• Protein Isoforms genetics   metabolism   MeSH
• ras GTPase-Activating Proteins genetics   metabolism   MeSH
• Protein Tyrosine Phosphatase, Non-Receptor Type 11 genetics   metabolism   MeSH
• Gene Silencing MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH