TY - JOUR
T1 - RASA4 undergoes DNA hypermethylation in resistant juvenile myelomonocytic leukemia
AU - Poetsch, Anna R.
AU - Lipka, Daniel B.
AU - Witte, Tania
AU - Claus, Rainer
AU - Nöllke, Peter
AU - Zucknick, Manuela
AU - Olk-Batz, Christiane
AU - Fluhr, Silvia
AU - Dworzak, Michael
AU - De Moerloose, Barbara
AU - Starý, Jan
AU - Zecca, Marco
AU - Hasle, Henrik
AU - Schmugge, Markus
AU - Van Den Heuvel-Eibrink, Marry M.
AU - Locatelli, Franco
AU - Niemeyer, Charlotte M.
AU - Flotho, Christian
AU - Plass, Christoph
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
KW - JMML
KW - epigenetics,juvenile myelomonocytic leukemia
KW - RASA4
KW - JMML
KW - epigenetics,juvenile myelomonocytic leukemia
KW - RASA4
UR - http://hdl.handle.net/10807/243259
U2 - 10.4161/epi.29941
DO - 10.4161/epi.29941
M3 - Article
SN - 1559-2294
VL - 9
SP - 1252
EP - 1260
JO - Epigenetics
JF - Epigenetics
ER -