RAS-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia.
RAS-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia.
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DOI：
10.1038/s41467-017-02177-w
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发表时间：
2017-12-19
影响因子：
16.6
通讯作者：
Plass C
中科院分区：
文献类型：
--
作者：
Lipka DB;Witte T;Toth R;Yang J;Wiesenfarth M;Nöllke P;Fischer A;Brocks D;Gu Z;Park J;Strahm B;Wlodarski M;Yoshimi A;Claus R;Lübbert M;Busch H;Boerries M;Hartmann M;Schönung M;Kilik U;Langstein J;Wierzbinska JA;Pabst C;Garg S;Catalá A;De Moerloose B;Dworzak M;Hasle H;Locatelli F;Masetti R;Schmugge M;Smith O;Stary J;Ussowicz M;van den Heuvel-Eibrink MM;Assenov Y;Schlesner M;Niemeyer C;Flotho C;Plass C
幼年粒单核细胞白血病(JMML)是一种儿童早期侵袭性骨髓增生性疾病，其特征是突变激活RAS信号。已建立的临床和遗传标记不能完全概括这种疾病的临床和生物学异质性。在这里，我们报告了167例JMML样本的DNA甲基组分析和突变谱分析。我们确定了三个具有独特分子和临床特征的JMML亚群。高甲基化组(HM)以PTPN11体细胞突变和临床预后差为特征。低甲基化组体细胞NRAS和CBL突变丰富，Noonan患者也是如此，预后良好。中间甲基化组(IM)显示单体7和体细胞KRAS突变丰富。高甲基化与染色质抑制、RAS信号调节基因、RAS途径突变频繁共存以及DNMT1和Dnmt3b上调有关，提示DNA甲基化机制的激活与JMML的突变模式之间存在联系。青少年粒单核细胞白血病(JMML)是一种侵袭性疾病，治疗选择有限。在这里，作者分析了JMML的DNA甲基组和突变谱，以确定具有独特分子和临床特征的三个亚组。
Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative disorder of early childhood characterized by mutations activating RAS signaling. Established clinical and genetic markers fail to fully recapitulate the clinical and biological heterogeneity of this disease. Here we report DNA methylome analysis and mutation profiling of 167 JMML samples. We identify three JMML subgroups with unique molecular and clinical characteristics. The high methylation group (HM) is characterized by somatic PTPN11 mutations and poor clinical outcome. The low methylation group is enriched for somatic NRAS and CBL mutations, as well as for Noonan patients, and has a good prognosis. The intermediate methylation group (IM) shows enrichment for monosomy 7 and somatic KRAS mutations. Hypermethylation is associated with repressed chromatin, genes regulated by RAS signaling, frequent co-occurrence of RAS pathway mutations and upregulation of DNMT1 and DNMT3B, suggesting a link between activation of the DNA methylation machinery and mutational patterns in JMML. Juvenile myelomonocytic leukemia (JMML) is an aggressive disease with limited options for treatment. Here, the authors analyse the DNA methylome and mutational profile of JMML to define three subgroups with unique molecular and clinical characteristics.
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