RASA4 undergoes DNA hypermethylation in resistant juvenile myelomonocytic leukemia
RASA4 undergoes DNA hypermethylation in resistant juvenile myelomonocytic leukemia
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DOI：
10.4161/epi.29941
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发表时间：
2014-09-01
期刊：
影响因子：
3.7
通讯作者：
Plass, Christoph
中科院分区：
文献类型：
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作者：
Poetsch, Anna R.;Lipka, Daniel B.;Plass, Christoph
特定基因位点的异常甲基化是幼年粒单核细胞白血病（JMML）预后不良的关键分子特征。使用定量高分辨率质谱，我们确定RASA 4亚型2，它映射到7号染色体，编码小G蛋白的GTP酶激活蛋白的GAP 1家族成员，作为JMML中亚型特异性DNA超甲基化的复发靶点（分析的125例患者中的51%）。RASA4亚型2启动子甲基化与预测预后不良（年龄较大，胎儿血红蛋白升高）的临床参数相关，造血干细胞移植后复发风险较高，并与PTPN11突变相关。同种型2甲基化水平在移植后复发病例中增加。有趣的是，大多数具有单体7的JMML病例在剩余的RASA 4等位基因上表现出高甲基化。结果证实了表观遗传修饰在侵袭性JMML表型中的重要性。
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.